RIP1 inhibitory compounds and methods for making and using the same

ABSTRACT

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing dates of U.S.provisional application No. 62/897,223, filed on Sep. 6, 2019, U.S.Provisional Application No. 62/932,404, filed on Nov. 7, 2019, U.S.Provisional Application No. 63/004,290, filed on Apr. 2, 2020, U.S.Provisional Application No. 63/001,016, filed on Mar. 27, 2020, U.S.Provisional Application No. 63/004,301, filed on Apr. 2, 2020, and U.S.Provisional Application No. 63/004,319, filed on Apr. 2, 2020.

FIELD

The present disclosure concerns compounds and methods of making andusing the compounds, such as for inhibiting receptor-interactingprotein-1 kinase (“RIP1”), and for treating diseases and/or conditionsrelated to RIP1.

BACKGROUND

Receptor-interacting protein-1 kinase (referred to herein as “RIP1”)belongs to the tyrosine kinase-like family and is a serine/threonineprotein kinase involved in innate immune signaling. RIP1 plays a centralrole in regulating cell signaling and its role in programmed cell deathhas been linked to various inflammatory diseases, such as inflammatorybowel disease, psoriasis, and other diseases and/or conditionsassociated with inflammation and/or necroptotic cell death.

SUMMARY

Disclosed compounds according to the present disclosure may have aFormula I

or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, orstereoisomer thereof. With reference to Formula 1, ring B is 5-memberedor 6-membered heteroaryl wherein the heteroaryl has at least one ringatom and the remainder of the ring atoms are carbon; L is a heteroatomor R^(a), provided that R^(a) is not H or D; Z is C₁₋₁₀aliphatic,including cycloaliphatic, or aryl; each R¹ independently is a halogen,—C≡CH, or a -linker-R⁶ group, wherein the linker is a bond or R^(a)provided that R^(a) is not H or D, and R is heterocyclyl, R, —C(R^(f))₃,or —C(R^(f))═C(R^(f))₂; R² is R^(a); R³ is R^(a); each R⁴ independentlyis R^(e); R^(a) is independently for each occurrence H or D, except forembodiments where L is R^(a), C₁₋₁₀aliphatic, C₁₋₁₀haloaliphatic,C₁₋₁₀heteroaliphatic, C₅₋₁₀aryl, C₃₋₆cycloaliphatic, orC₃₋₆heterocycloaliphatic; R is independently for each occurrence —OH,—SH, —OR^(c), —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c),—C(O)NR^(d)R^(d), —OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl substituted withone or two NR^(d)R^(d), carboxyl, or a combination thereof, andoptionally further substituted with an aromatic moiety, —SH, —O-acyl, or—C(O)NH₂; R^(c) is independently for each occurrence C₁₋₁₀alkyl,optionally substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, optionallysubstituted with 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, optionally substitutedwith 1, 2 or 3 R^(e), C₃₋₆cycloalkyl, optionally substituted with 1, 2or 3 R^(e), or C₅₋₁₀aromatic, optionally substituted with 1, 2 or 3R^(e); R^(d) is independently for each occurrence H; C₁₋₆alkyl,optionally substituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl;C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);C₃₋₉heterocyclic, optionally substituted with 1, 2 or 3 R^(e);C₅₋₁₀aryl, optionally substituted with 1, 2 or 3 R^(b); C₅₋₁₀heteroaryl,optionally with 1, 2 or 3 R^(e); or two R^(d) groups together with thenitrogen bound thereto provide a C₃₋₉heterocyclic, optionallysubstituted with one or more R^(e), or a C₅₋₁₀heteroaryl, optionallywith one or more R^(e); R^(e) is independently for each occurrencehalogen, C₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₅₋₁₀heteroaryl, or —OR^(a); and R is independently foreach occurrence -alkyl-phosphate, R^(a), R^(b), or R^(e), or two R^(f)groups together with the carbon atom bound thereto provide a C₂₋₆alkenylgroup, a C₃₋₆cycloalkyl group, optionally substituted with one or moreR^(e), or a C₃₋₁₀heterocyclic, optionally with one or more R^(e) oracyl; m is 1, 2, 3, or 4; and n is 0, 1 or 2.

For certain embodiments, the compound is not:I-56-(S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;I-64-(S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;I-68-(S)—N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;I-72-(S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;orI-77-(S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.In certain other embodiments, the compound is not I-1 through I-97 orI-187 through I-189.

For certain embodiments, ring B is pyrazolyl or pyridinyl. For example,when ring B is pyrazolyl or pyridinyl, L may be a heteroatom orC₁₋₁₀aliphatic; Z may be C₁₋₁₀aliphatic or aryl; each R¹ may beheterocyclyl or C₁₋₁₀aliphatic; R² may be H or C₁₋₁₀aliphatic; R³ may beH or C₁₋₁₀aliphatic; each R⁴ independently may be halogen orC₁₋₁₀aliphatic; m may be 1, 2, 3, or 4; and n may be 0, 1 or 2. A personof ordinary skill will appreciate that compounds of all stereoisomersare included in Formula 1, including but not limited to, compoundshaving a formula

With reference to particular exemplary embodiments of disclosedpyridine- and pyrazole-type compounds, such compounds may have a formulaas indicated below, including any and all stereoisomers thereof:

With reference to each of the preceding general formulas, particularcompounds have R² and/or R³ as H or C₁₋₆alkyl, such as methyl; each R⁴independently as halogen or C₁₋₆alkyl, such as chloro, fluoro or methyl;n is 0, 1 or 2; L is a heteroatom, such as oxygen, or C₁₋₁₀alkyl orC₁₋₆alkyl, such as —CH₂—; and Z is aryl or C₃₋₆cycloalkyl.

For particular compounds, Z is

where each independently is R^(e) and p is 0, 1, 2, 3, 4, or 5. Forexample, each R independently may be halogen or C₁₋₆alkyl, such asfluoro or methyl. Z also may be C₁₋₆alkyl, such as methyl; orcycloalkyl, such as cyclobutyl or cyclopentyl. For certain embodiments,the -L-Z moiety is.phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy,2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl,2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy,4-methylphenoxy, or benzyl.

For particular compounds, each R¹ independently is heterocyclyl,unsubstituted C₁₋₁₀aliphatic, or C₁₋₁₀aliphatic substituted with one ortwo substituents selected from —OH, halogen, carboxyl, carboxyl ester,heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl,—OC(O)NH(C₁₋₄alkyl)-amino, —OC(O)R⁸; or —OC(O)(CHR⁹)₂CO₂H. The —OC(O)—R⁸substituent may be derived from an amino acid, particularly naturallyoccurring amino acid, where the —OC(O)— moiety of —OC(O)—R⁸ correspondsto an acid moiety on the amino acid and R⁸ comprises —N(R¹⁰)₂ or anitrogen-containing nonaromatic heterocyclyl, where R¹⁰ is H or carboxylester. R¹ also may be a C₁₋₁₀alkyne or a substituted alkyne, such as analkyne substituted with hydroxyl, oxetanyl, azetidinyl, pyridinyl,pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate. R¹ also maybe a 8- to 12-membered spiroheterocyclyl.

Exemplary disclosed compounds include compounds I-98 through I-211 andII-1 through II-61, and including picolinamide compounds I-98 throughI-174, I-177, and I-190 through I-211; and pyrazole compounds I-175, andI-178 through I-184.

Disclosed embodiments also include pharmaceutical compositionscomprising disclosed compounds. Such compositions may further comprisean excipient, an additional therapeutic agent, or combinations thereof.

A method may comprise administering to a subject a disclosed compound orcompounds, or a composition comprising a disclosed compounds orcompounds, such as to treat a disease. In some embodiments, the subjectmay have, or may be suspected of having or developing, the disease, suchas a disease involving a receptor-interacting protein-1 (RIP1) kinase.Examples of diseases that can be treated according to this methodembodiment include diseases or disorders associated with inflammation,necroptosis, or both. In certain embodiments, diseases to be treatedwith the present compounds are inflammatory or immune-regulatorydisorders, including autoimmune and proliferative disorders. Exemplarydiseases are disclosed herein.

The foregoing and other objects and features of the present disclosurewill become more apparent from the following detailed description.

DETAILED DESCRIPTION I. Overview of Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is expressly recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

If an R group is depicted as “floating” on a ring system, as for examplewith R¹ in the group:

then, unless otherwise defined, a substituent R (e.g., R¹ above) canreside on any atom of the fused bicyclic ring system, excluding the atomcarrying the bond with the “

” symbol, so long as a stable structure is formed.

When a group R is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, y can be more than one, assuming each replaces acurrently depicted, implied, or expressly defined hydrogen on the ring;then, unless otherwise defined, two R's can reside on the same carbon. Asimple example is when R is a methyl group. The depicted structure canexist as a geminal dimethyl on a carbon of the depicted ring (an“annular” carbon). In another example, two R's on the same carbon,including that same carbon, can be included in a ring, thus creating aspirocyclic ring (a “spirocyclyl” group) structure.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted unless the context indicates otherwise or aparticular structural formula precludes substitution. In particularembodiments, a substituent may or may not be expressly defined assubstituted, but is still contemplated to be optionally substituted. Forexample, an “aliphatic” or a “cyclic” moiety may be unsubstituted orsubstituted, but an “unsubstituted aliphatic” or an “unsubstitutedcyclic” is not substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety can be, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₁₀aliphatic, heteroaliphatic, or cycloaliphatic, typically,C₁₋₆aliphatic, more typically C₁₋₆alkyl, where R⁶⁰ optionally may besubstituted; each R⁷⁰ is independently for each occurrence hydrogen orR⁶⁰; each R⁸⁰ is independently for each occurrence R⁷⁰ or alternatively,two R⁸⁰ groups, taken together with the nitrogen atom to which they arebonded, form a 3- to 7-membered heterocycloaliphatic, which optionallyincludes from 1 to 4 of the same or different additional heteroatomsselected from O, N and S, of which N optionally has R⁷⁰ substitution,such as H or C₁-C₃alkyl substitution; and each M⁺ is a counter ion witha net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as ⁺N(R⁶⁰)₄; a protonated amino acid ion, such as alysine ion, or an arginine ion; or an alkaline metal earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a subscript “0.5” means,for example, that one of the counter ions for such divalent alkali earthions can be an ionized form of a compound of the disclosure and theother a typical counter ion such as chloride, or two ionized compoundscan serve as counter ions for such divalent alkali earth ions, or adoubly ionized compound can serve as the counter ion for such divalentalkali earth ions). As specific examples, —N(R⁸⁰)₂ includes —NH₂,—NH-alkyl, —NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon also can be replaced with, for example, ═O,═NR⁷⁰, ═N—OR⁷⁰, ═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M+,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined. In an independent embodiment, the substituentsare not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰,—PO₃ ²⁻(M⁺)₂, —P₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined.

In one embodiment, a group that is substituted has at least onesubstituent up to the number of substituents possible for a particularmoiety, such as 1 substituent, 2 substituents, 3 substituents, or 4substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

Any group or moiety defined herein can be connected to any other portionof a disclosed structure, such as a parent or core structure, as wouldbe understood by a person of ordinary skill in the art, such as byconsidering valence rules, comparison to exemplary species, and/orconsidering functionality, unless the connectivity of the group ormoiety to the other portion of the structure is expressly stated, or isimplied by context.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, or aromatic (including both aryl and heteroaryl).Exemplary acyl moieties include, but are not limited to, —C(O)H,—C(O)alkyl, —C(O)C₁-C₆alkyl, —C(O)C₁-C₆haloalkyl, —C(O)cycloalkyl,—C(O)alkenyl, —C(O)cycloalkenyl, —C(O)aryl, —C(O)heteroaryl, or—C(O)heterocyclyl. Specific examples include, —C(O)H, —C(O)Me, —C(O)Et,or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety.An aliphatic group or moiety can be acyclic, including alkyl, alkenyl,or alkynyl groups (as well as alkylene, alkenylene, or alkynylenegroups), cyclic versions thereof, such as cycloaliphatic groups ormoieties including cycloalkyl, cycloalkenyl or cycloalkynyl, and furtherincluding straight- and branched-chain arrangements, and all stereo andposition isomers as well. Unless expressly stated otherwise, analiphatic group contains from one to twenty-five carbon atoms (C₁₋₂₅);for example, from one to fifteen (C₁₋₁₅), from one to ten (C₁₋₁₀) fromone to six (C₁₋₆), or from one to four carbon atoms (C_(1_4)) for anacyclic aliphatic group or moiety, or from three to fifteen (C₃₋₁₅) fromthree to ten (C₃₋₁₀), from three to six (C₃₋₆), or from three to four(C₃₋₄) carbon atoms for a cycloaliphatic group or moiety. An aliphaticgroup may be substituted or unsubstituted, unless expressly referred toas an “unsubstituted aliphatic” or a “substituted aliphatic.” Analiphatic group can be substituted with one or more substituents (up totwo substituents for each methylene carbon in an aliphatic chain, or upto one substituent for each carbon of a —C═C— double bond in analiphatic chain, or up to one substituent for a carbon of a terminalmethine group).

“Lower aliphatic” refers to an aliphatic group containing from one toten carbon atoms (C₁₋₁₀), such as from one to six (C₁₋₆), or from one tofour (C₁₋₄) carbon atoms; or from three to ten (C_(3_10)), such as fromthree to six (C₃₋₆) carbon atoms for a lower cycloaliphatic group.

“Alkoxy” refers to the group —OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group.In certain examples R is a C₁₋₆ alkyl group or a C₃₋₆cycloalkyl group.Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃) are exemplary alkoxy groups. In asubstituted alkoxy, R is substituted alkyl or substituted cycloalkyl,examples of which in the presently disclosed compounds includehaloalkoxy groups, such as —OCF₂H.

“Alkoxyalkyl” refers to the group -alkyl-OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group;—CH₂CH₂—O—CH₂CH₃ is an exemplary alkoxyalkyl group.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to at least 25 (C₁₋₂₅) carbon atoms, more typically 1 to 10 (C₁₋₁₀)carbon atoms such as 1 to 6 (C₁₋₆) carbon atoms. An alkyl moiety may besubstituted or unsubstituted. This term includes, by way of example,linear and branched hydrocarbyl groups such as methyl (CH₃), ethyl(—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aromatic,including both aryl and heteroaryl, or heterocycloaliphatic, or two Rgroups together with the nitrogen attached thereto form a heterocyclicring. Examples of such heterocyclic rings include those wherein two Rgroups together with the nitrogen to which they are attached form a—(CH₂)₂₋₅— ring optionally interrupted by one or two heteroatom groups,such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(R)acyl, wherein R is hydrogen,heteroaliphatic, or aliphatic, such as alkyl, particularly C₁₋₆alkyl.

“Aromatic” refers to a cyclic, conjugated group or moiety of, unlessspecified otherwise, from 5 to 15 ring atoms having a single ring (e.g.,phenyl, pyridinyl, or pyrazolyl) or multiple condensed rings in which atleast one ring is aromatic (e.g., naphthyl, indolyl, orpyrazolopyridinyl), that is at least one ring, and optionally multiplecondensed rings, have a continuous, delocalized π-electron system.Typically, the number of out of plane π-electrons corresponds to theHückel rule (4n+2). The point of attachment to the parent structuretypically is through an aromatic portion of the condensed ring system.For example,

However, in certain examples, context or express disclosure may indicatethat the point of attachment is through a non-aromatic portion of thecondensed ring system. For example,

An aromatic group or moiety may comprise only carbon atoms in the ring,such as in an aryl group or moiety, or it may comprise one or more ringcarbon atoms and one or more ring heteroatoms comprising a lone pair ofelectrons (e.g. S, O, N, P, or Si), such as in a heteroaryl group ormoiety. Unless otherwise stated, an aromatic group may be substituted orunsubstituted.

“Aryl” refers to an aromatic carbocyclic group of, unless specifiedotherwise, from 6 to 15 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings in which at least one ring is aromatic(e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If anyaromatic ring portion contains a heteroatom, the group is heteroaryl andnot aryl. Aryl groups may be, for example, monocyclic, bicyclic,tricyclic or tetracyclic. Unless otherwise stated, an aryl group may besubstituted or unsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Carboxyl” refers to —CO₂H.

“Carboxamide” refers to —C(O)amino.

“Carboxyl ester” or “carboxy ester” refers to the group C(O)OR, where Ris aliphatic, heteroaliphatic, or aromatic (including both aryl andheteroaryl).

“Carboxylate” refers to —C(O)O⁻ or salts thereof.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, the ring or at least one of the rings in the systemis aliphatic. Typically, the point of attachment to the parent structureis through an aliphatic portion of the multiple ring system.Cycloaliphatic includes saturated and unsaturated systems, includingcycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group maycontain from three to twenty-five carbon atoms; for example, from threeto fifteen, from three to ten, or from three to six carbon atoms. Unlessotherwise stated, a cycloaliphatic group may be substituted orunsubstituted. Exemplary cycloaliphatic groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, or cyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl moiety substituted with one or morehalogens. Exemplary haloalkyl moieties include CH₂F, —CHF₂ and —CF₃.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom and at least one carbon atom, i.e., at least onecarbon atom from an aliphatic compound or group comprising at least twocarbon atoms, has been replaced with an atom having at least one lonepair of electrons, typically nitrogen, oxygen, phosphorus, silicon, orsulfur. Heteroaliphatic compounds or groups may be substituted orunsubstituted, branched or unbranched, chiral or achiral, and/or acyclicor cyclic, such as a heterocycloaliphatic group.

“Heteroaryl” refers to an aromatic group or moiety having, unlessspecified otherwise, from 5 to 15 ring atoms comprising at least onecarbon atom and at least one heteroatom, such as N, S, O, P, or Si. Aheteroaryl group or moiety may comprise a single ring (e.g., pyridinyl,pyrimidinyl or pyrazolyl) or multiple condensed rings (e.g., indolyl,benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moiety maybe, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unlessotherwise stated, a heteroaryl group or moiety may be substituted orunsubstituted.

“Heterocyclyl,” “heterocyclo” and “heterocycle” refer to both aromaticand non-aromatic ring systems, and more specifically refer to a stablethree- to fifteen-membered ring moiety comprising at least one carbonatom, and typically plural carbon atoms, and at least one, such as fromone to five, heteroatoms. The heteroatom(s) may be nitrogen, phosphorus,oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be amonocyclic moiety, or may comprise multiple rings, such as in a bicyclicor tricyclic ring system, provided that at least one of the ringscontains a heteroatom. Such a multiple ring moiety can include fused orbridged ring systems as well as spirocyclic systems; and any nitrogen,phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moietycan be optionally oxidized to various oxidation states. For convenience,nitrogens, particularly, but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.Thus, for a compound having, for example, a pyridinyl ring, thecorresponding pyridinyl-N-oxide is included as another compound of thedisclosure, unless expressly excluded or excluded by context. Inaddition, annular nitrogen atoms can be optionally quaternized.Heterocycle includes heteroaryl moieties, and heteroalicyclyl orheterocycloaliphatic moieties, which are heterocyclyl rings that arepartially or fully saturated. Examples of heterocyclyl groups include,but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic, such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; —O-aralkyl; or—OR′ is —O⁻M⁺, where M⁺ is a counter ion with a single positive charge.Each M⁺ may be an alkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonooxyalkyl refers tothe group -alkyl-phosphate, such as, for example, —CH₂OP(O)(OH)₂, or asalt thereof, such as —CH₂OP(O)(O⁻Na⁺)₂, and(((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of aphosphonooxyalkyl group, such as, for example, —CH₂P(O)(O-tert-butyl)₂.

“Phosphonate” refers to the group —P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; or —O-aralkyl; or—OR′ is —O⁻M⁺, and M⁺ is a counter ion with a single positive charge.Each M⁺ is a positively charged counterion and may be, by way ofexample, an alkali metal ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth metal ion,such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonoalkylrefers to the group alkyl-phosphonate, such as, for example,—CH₂P(O)(OH)₂, or —CH₂P(O)(O⁻Na⁺)₂, and ((dialkoxyphosphoryl)alkyl)refers to the dialkyl ester of a phosphonoalkyl group, such as, forexample, —CH2P(O)(O-tert-butyl)₂.

“Patient” or “Subject” may refer generally to any living being, but moretypically refers to mammals and other animals, particularly humans. Thusdisclosed methods are applicable to both human therapy and veterinaryapplications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient, that is included in a composition comprisingthe active ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, anti-adherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, carriers or vehicles.Excipients may be starches and modified starches, cellulose andcellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is a component that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as Freund's complete adjuvant orFreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Remington: The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, Pa., 21^(st) Edition (2005),incorporated herein by reference, describes exemplary compositions andformulations suitable for pharmaceutical delivery of one or moretherapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like.

“Pharmaceutically acceptable acid addition salts” are a subset of“pharmaceutically acceptable salts” that retain the biologicaleffectiveness of the free bases while formed by acid partners. Inparticular, the disclosed compounds form salts with a variety ofpharmaceutically acceptable acids, including, without limitation,inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, as well as organicacids such as amino acids, formic acid, acetic acid, trifluoroaceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid,isethionic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like.“Pharmaceutically acceptable base addition salts” are a subset of“pharmaceutically acceptable salts” that are derived from inorganicbases such as sodium, potassium, lithium, ammonium, calcium, magnesium,iron, zinc, copper, manganese, aluminum salts and the like. Exemplarysalts are the ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharmaceutically acceptable organic bases include,but are not limited to, salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the compounds may be a formate, trifluoroactate,hydrochloride or sodium salt.

“Effective amount” with respect to a compound or pharmaceuticalcomposition refers to an amount of the compound or pharmaceuticalcomposition sufficient to achieve a particular desired result, such asto inhibit a protein or enzyme. In particular embodiments, an “effectiveamount” is an amount sufficient to inhibit RIP1; to elicit a desiredbiological or medical response in a tissue, system, subject or patient;to treat a specified disorder or disease; to ameliorate or eradicate oneor more of its symptoms; and/or to prevent the occurrence of the diseaseor disorder. The amount of a compound which constitutes an “effectiveamount” may vary depending on the compound, the desired result, thedisease state and its severity, the size, age, and gender of the patientto be treated and the like, as will be understood by a person ofordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, or a compound more biologically activethan the parent compound. In vivo transformation may occur, for example,by hydrolysis or enzymatic conversion. Common examples of prodrugmoieties include, but are not limited to, ester and amide forms of acompound having an active form bearing a carboxylic acid moiety.Examples of pharmaceutically acceptable esters of the compounds of thisdisclosure include, but are not limited to, esters of phosphate groupsand carboxylic acids, such as aliphatic esters, particularly alkylesters (for example C₁₋₆alkyl esters). Other prodrug moieties includephosphate esters, such as —CH₂O—P(O)(OR′)₂ or a salt thereof, wherein R′is H or C₁₋₆alkyl. Acceptable esters also include cycloalkyl esters andarylalkyl esters such as, but not limited to benzyl. Examples ofpharmaceutically acceptable amides of the compounds of this disclosureinclude, but are not limited to, primary amides, and secondary andtertiary alkyl amides (for example with between about one and about sixcarbons). Amides and esters of disclosed exemplary embodiments ofcompounds according to the present disclosure can be prepared accordingto conventional methods. A thorough discussion of prodrugs is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of a solute. The solvent can be an organicsolvent, an inorganic solvent, or a mixture of both. Exemplary solventsinclude, but are not limited to, alcohols, such as methanol, ethanol,propanol; amides such as N,N-dialiphatic amides, such asN,N-dimethylformamide; tetrahydrofuran; alkylsulfoxides, such asdimethylsulfoxide; water; and combinations thereof. The compoundsdescribed herein can exist in un-solvated as well as solvated forms whencombined with solvents, pharmaceutically acceptable or not, such aswater, ethanol, and the like. Solvated forms of the presently disclosedcompounds are within the scope of the embodiments disclosed herein.

“Sulfonamide” refers to the group or moiety —SO₂amino, or —N(R)sulfonyl,where R is H, aliphatic, heteroaliphatic, or aromatic (including botharyl and heteroaryl).

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-heteroaliphatic,—S-aromatic, (including both —S-aryl and —S-heteroaryl).

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)heteroaliphatic, or —S(O)aromatic (including both —S(O)aryl and—S(O)heteroaryl).

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic,—SO₂heteroaliphatic, —SO₂aromatic (including both —SO₂aryl and—SO₂heteroaryl).

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, particularly a humanhaving the disease or condition of interest, and includes by way ofexample, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingdiminution of a symptom or regression of the disease or condition or asymptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, a person of ordinary skill in the art will appreciatethat the disclosed compounds encompass any tautomeric, conformationalisomeric, optical isomeric, and/or geometric isomeric forms of thecompounds described herein, as well as mixtures of these variousdifferent isomeric forms. Mixtures of different isomeric forms,including mixtures of enantiomers and/or stereoisomers, can be separatedto provide each separate enantiomers and/or stereoisomer usingtechniques known to those of ordinary skill in the art, particularlywith the benefit of the present disclosure. In cases of limitedrotation, e.g. around the amide bond or between two directly attachedrings such as pyridinyl rings, biphenyl groups, and the like,atropisomers are also possible and are also specifically included in thecompounds of the disclosure.

In any embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be replaced by adeuterium or a tritium. Thus, a recitation of alkyl includes deuteratedalkyl, where from one to the maximum number of hydrogens present may bereplaced by deuterium. For example, ethyl refers to both C₂H₅ or C₂H₅where from 1 to 5 hydrogens are replaced by deuterium, such as inC₂D_(x)H_(5-x).

II. RIP1-Active Compounds and Pharmaceutical Compositions ComprisingRIP1-Active Compounds

A. Compounds

Disclosed herein are compounds and pharmaceutical compositionscomprising such compounds that are useful for inhibiting RIP1 and/or fortreating diseases and/or conditions associated with RIP1. In someembodiments, the compounds are selective kinase inhibitors. For example,exemplary compounds are able to selectively inhibit RIP1 over RIP2,RIP3, or both RIP2 and RIP3.

In some embodiments, a compound of the present disclosure has astructure according to Formula I

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that compounds within the scope ofFormula I also include stereoisomers, N-oxides, tautomers, hydrates,solvates, isotopes, and/or prodrugs thereof, unless otherwise specified.With respect to Formula I, ring B is heteroaryl, such as a 5-membered or6-membered heteroaryl. In some embodiments, ring B is a 5-membered or6-membered heteroaryl wherein the heteroaryl has at least one ringnitrogen atom, and perhaps one, two or three ring nitrogen atoms, andthe remainder of the ring atoms are carbon. In some embodiments, the Bring does not include three ring nitrogen atoms, and ring B is not atriazole, triazine, or a heteroaryl comprising an oxygen or sulfur ringatom, such as oxazole, thiazole or isoxazole. In certain embodiments,ring B is pyrazolyl, and in other particular embodiments, ring B ispyridinyl.

Each R¹ independently may be halogen, —C≡CH, or a -linker-R⁶ group,wherein the linker is a bond or R^(a), provided that R^(a) is not H orD, and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂.

R² is R^(a).

R³ is R^(a).

If present, each R⁴ independently is R^(e).

L is a heteroatom or R^(a), provided that R^(a) is not H or D.

Z, if present, is aryl or cycloaliphatic, including cycloalkyl, such asa C₃₋₆cycloalkyl;

m is 1, 2, 3, or 4, and n is 0, 1 or 2.

R^(a) is independently for each occurrence H or D, except forembodiments where L is R^(a), C₁₋₁₀aliphatic, C₁₋₁₀haloaliphatic,C₁₋₁₀heteroaliphatic, C₅₋₁₀aryl, C₃₋₆cycloaliphatic, orC₃₋₆heterocycloaliphatic.

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR, —C(O)NR^(d)R^(d),—OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl substituted with one or twoNR^(d)R^(d), carboxyl, or a combination thereof, and optionally furthersubstituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH₂.

R^(c) is independently for each occurrence C₁₋₁₀alkyl, which can besubstituted with 1, 2 or 3 R^(e); C₂₋₁₀alkenyl, which can be substitutedwith 1, 2 or 3 R^(e); C₂₋₁₀alkynyl, which can be substituted with 1, 2or 3 R^(e); C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3R^(e); or C₅₋₁₀aromatic, which can be substituted with 1, 2 or 3 R^(e).

R^(d) is independently for each occurrence H; C₁₋₆alkyl, which can besubstituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl; C₃₋₆cycloalkyl,which can be substituted with 1, 2 or 3 R^(e); C₃₋₆heterocyclic, whichcan be substituted with 1, 2 or 3 R^(e); C₅₋₁₀aryl, which can besubstituted with 1, 2 or 3 R^(b); C₅₋₁₀heteroaryl, which can besubstituted with 1, 2 or 3 R^(e); or two R^(d) groups together with thenitrogen bound thereto provide a C₃₋₉heterocyclic, which can besubstituted with one or more R^(e); or a C₅₋₁₀heteroaryl, which can besubstituted with one or more R.

R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₅₋₁₀heteroaryl, or —OR^(a).

And R^(f) is independently for each occurrence -alkyl-phosphate, R^(a),R^(b), or R^(e), or two R^(f) groups together with the carbon atom boundthereto provide a C₂₋₆alkenyl group, a C₃₋₆cycloalkyl group, which canbe substituted with one or more R^(e), or a C₃₋₁₀heterocyclic, which canbe substituted with one or more R^(e) or acyl.

In some embodiments of Formula I, the compound is not any one ofcompounds I-1 though I-97 or I-187 to I-189. In other embodiments, thecompound is not:

-   I-56:    (S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-64:    (S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-68:    (S)—N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-72:    (S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;    or-   I-77:    (S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.

In an independent embodiment, the compound is not any of the following:

-   (S)—N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;-   (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   N—((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;-   N—((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-1-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5    tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;-   (S)-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;-   (S)—N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)—N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)—N-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   (S)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;    and-   (S)-5-benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

In certain embodiments of Formula I, ring B is pyridinyl or pyrazolyl; Lis a heteroatom, such as oxygen, or C₁₋₁₀aliphatic, such asC₁₋₈aliphatic, including —CH₂ or substituted C₁₋₈aliphatic, such asC₁₋₈aliphatic substituted with cycloaliphatic, such as C₁₋₅cycloaliphatic, such as cyclopropyl; Z is aryl, with certain exemplaryembodiments being phenyl or substituted phenyl, or C₁₋₁₀aliphatic,including cycloaliphatic, such as cycloalkyl, with certain exemplaryembodiments being C₃₋₆cycloalkyl; each R¹ is heterocyclyl, orC₁₋₁₀aliphatic; R² is H or C₁₋₁₀aliphatic; R³ is H or C₁₋₁₀aliphatic;each R⁴ independently is halogen or C₁₋₁₀aliphatic; m is 1, 2, 3, or 4;and n is 0, 1 or 2.

In some embodiments, each R¹ independently is heterocyclyl,unsubstituted C₁₋₁₀aliphatic, or C₁₋₁₀aliphatic substituted with one ortwo substituents selected from —OH, halogen, carboxyl, carboxyl ester,heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl,—OC(O)NH(C₁₋₄alkyl)-amino, —OC(O)R⁸, or —OC(O)(CHR⁹)₂CO₂H. The —OC(O)—R⁸moiety may be derived from an amino acid where the —OC(O)— moiety of—OC(O)—R⁸ corresponds to an acid moiety on the amino acid and R⁸comprises —N(R¹⁰)₂ or a nitrogen-containing nonaromatic heterocyclyl,where R¹⁰ is H or carboxyl ester. And each R⁹ independently is H or—O-acyl.

With respect to the —OC(O)—R⁸ moiety, the nitrogen-containingnonaromatic heterocyclyl may be a 5- or 6-membered unsaturatednitrogen-containing heterocyclyl, for example, pyrrolidinyl. The aminoacid can be any amino acid, such as a naturally occurring amino acid,and may be an amino acid selected from glycine, valine, alanine,leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine,serine, threonine, asparagine, glutamine, arginine, histidine, lysine,aspartic acid, glutamic acid, cysteine, or proline. A person of ordinaryskill in the art will understand that if the amino acid comprises one ormore chiral center, all enantiomers, diastereomers and/or mixturesthereof are contemplated. For example, the amino acid may be the L-aminoacid, the D-amino acid or a mixture thereof. In some embodiments, theamino acid is the L-amino acid. And in certain embodiments, —OC(O)—R⁸ is—OC(O)CH(NH₂)R¹¹,

or —OC(O)—(CH₂)₁₋₂C(NH₂)CO₂H, where R¹¹ is an amino acid side chain,and/or may be H, —CH₃, isopropyl, —CH₂CH(CH₃)₂, —CH(CH₃)Et, —CH₂CH₂SCH₃,

—CH₂OH, —CH(OH)CH₃, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂SH,—CH₂CH₂CH₂NHC(O)(NH)NH₂,

—CH₂CH₂CH₂CH₂NH₂, —CH₂CO₂H, or CH₂CH₂CO₂H.

With respect to R¹, at least one R¹ may be an 8- to 12-memberedspiroheterocyclyl or a C₁₋₁₀alkyne. The C₁₋₁₀alkyne may includesubstituents, such as one or two substituents. One particular exemplarysubstituent may be —OH. In some embodiments, one substituent isoxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl,tetrahydropyranyl, or phosphate, and/or in some embodiments, onesubstituent is —OC(O)—R⁸.

In some embodiments, m is 1, 2 or 3, and may be 1 or 2, and in certainembodiments, m is 1.

R² may be H or C₁₋₆alkyl, such as methyl.

R³ may be H or C₁₋₆alkyl, and in certain embodiments, R³ is H.

Each R⁴ independently may be halogen, such as F, Br, Cl or I, orC₁₋₁₀aliphatic, such as C₁₋₆alkyl. In some embodiments, each R⁴independently is chloro, fluoro or methyl.

In certain embodiments n is 0, and in other particular embodiments, n is1.

Also with respect to Formula I, L may be a heteroatom or R^(a), providedthat R^(a) is not H or D. L may be oxygen or C₁₋₁₀alkyl, such asC₁₋₆alkyl, more particularly methylene (—CH₂—). Z is C₁₋₁₀aliphatic oraryl. In some embodiments, Z is C₃₋₆cycloalkyl, such as cyclobutyl orcyclopentyl, or C₁₋₆alkyl, such as methyl. In certain embodiments, the-L-Z moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy,2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy,4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy,methoxy, 4-methylphenoxy, or benzyl.

In some embodiments of Formula I, the compound may have a structureaccording to formulas I-1 or I-2:

In some embodiments, the compound may have a structure according to oneor more of the following formulas

With respect to Formulas I-1 to I-20, ring B, L, Z, R¹, R², R³, R⁴, mand n, if present, are as defined herein for Formula I.

In any of the above embodiments concerning Formula I and/or Formulas I-1through I-20, R¹ may be selected from any of the following:

And, in certain embodiments of Formula I and/or Formulas I-1 throughI-32, R¹ may be selected from any of the following:

In other embodiments of Formula I

ring B is 5-membered or 6-membered heteroaryl;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, orC₃₋₆cycloalkyl); or

R¹ is a halogen (—F, —Cl, —Br, —I)—C≡CH, or a -linker-R group, whereinthe linker is R^(a), provided that R^(a) is not H or D, and R⁶ is R^(b),—C(R^(f))₃, or —C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R⁵ independently are R^(e);

R^(a) is independently for each occurrence H or D (except forembodiments where L is R^(a)), C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl), C₁₋₁₀haloaliphatic,C₅₋₁₀aryl, C₃₋₆cycloaliphatic or C₃₋₆heterocycloaliphatic;

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(d)R^(d);

R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can besubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can besubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can besubstituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can besubstituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can besubstituted with 1, 2 or 3 R^(e));

R^(d) is independently for each occurrence H; C₁₋₆alkyl(which can besubstituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which can besubstituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic (which can besubstituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl (which can be substitutedwith 1, 2 or 3 R^(b)); C₅₋₁₀ heteroaryl (which can be substituted with1, 2 or 3 R^(e)); or two R groups together with the nitrogen boundthereto provide a C₃₋₉heterocyclic (which can be substituted with one ormore R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one ormore R^(e));

R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₅₋₁₀heteroaryl, or —OR^(a); and

R^(f) is independently for each occurrence R^(a), R^(b), or R^(e), ortwo R^(f) groups together with the carbon atom bound thereto provide aC₃₋₆cycloalkyl group (which can be substituted with one or more R^(e)),or a C₃₋₁₀heterocyclic (which can be substituted with one or moreR^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

p is 0, 1, 2, 3, 4, or 5.

In some embodiments, a compound of the present disclosure can have astructure satisfying Formula IA

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that the disclosed general formulasinclude within their scope all stereoisomers, N-oxides, tautomers,hydrates, solvates, isotopes, and/or prodrugs of compounds otherwisehaving structural features required by such formulas.

With reference to Formula IA:

ring B is 5-membered or 6-membered heteroaryl;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

R¹ is a halogen, —C≡CH, or a -linker-R group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R, —C(R^(f))₃, or—C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R independently are R^(e);

R^(a) is independently for each occurrence H or D (except forembodiments where L is R^(a)), C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloaliphatic such asC₃₋₆cycloalkyl), C₁₋₁₀haloaliphatic, C₁₋₁₀heteroaliphatic, C₅₋₁₀aryl, orC₃₋₆heterocycloaliphatic, such as C₃₋₆heterocycloalkyl;

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(d)R^(d);

R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can besubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can besubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can besubstituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can besubstituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can besubstituted with 1, 2 or 3 R^(e));

R^(d) is independently for each occurrence H; C₁₋₆alkyl(which can besubstituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which can besubstituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic (which can besubstituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl (which can be substitutedwith 1, 2 or 3 R^(b)); C₅₋₁₀ heteroaryl (which can be substituted with1, 2 or 3 R^(e)); or two R^(d) groups together with the nitrogen boundthereto provide a C₃₋₉heterocyclic (which can be substituted with one ormore R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one ormore R^(e));

R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₅₋₁₀heteroaryl, or —OR^(a); and

R^(f) is independently for each occurrence R^(a), R^(b), or R^(e) or twoR^(f) groups together with the carbon atom bound thereto provide aC₃₋₆cycloalkyl group (and in some embodiments, the C₃₋₆cycloalkyl groupis substituted with one or more R^(e)), or a C₃₋₁₀heterocyclic (and insome embodiments, the C₃₋₁₀heterocyclic group is substituted with one ormore R^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

p is 0, 1, 2, 3, 4, or 5.

In particular embodiments of Formulas I or IA, the 5-membered heteroarylgroup can have structure satisfying formula

wherein at least one W is nitrogen, and each remaining W independentlyis selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In someembodiments, the 5-membered heteroaryl group is a diazole, a triazole,an oxadiazole, or an oxazole. Exemplary triazoles include any of thefollowing:

Exemplary diazoles are selected from any of the following:

Exemplary oxazoles are selected from any of the following:

Exemplary oxadiazoles are selected from any of the following:

In particular embodiments of Formulas I or IA, L is oxygen or R^(a)wherein R^(a) is C₁-C₄alkyl, such as —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—. In some embodiments, L is —CH₂— or oxygen.

The linker group of R¹ groups where R¹ is linker-R⁶ is a C₁, C₂, C₃, orC₄ aliphatic group, such a C₂ alkyl group, an alkenyl group, or analkynyl group, or a C₁, C₂, C₃, or C₄ haloaliphatic group, such as a C₂haloalkyl group, or an haloalkenyl group. In some embodiments, thelinker group of R¹ is R^(a) wherein R^(a) is C₁-C₄alkyl, such as —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—; or the linker group isC₂-C₄alkenyl, such as —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, or —CH₂CH═CHCH₂—;or the linker group is C₂-C₄alkynyl, such as —C≡C—, —C≡CCH₂—, —CH₂C≡C—,or —CHC≡C—CH₂—. In some embodiments, the linker group isC₂-C₄haloalkenyl, such as —CF═CH—, —CCl═CH—, —CH═CCl—, —CH═CF—,—CCl═CCl—, —CF═CF—, or —CCl═CF—, —CF═CCl—. In some embodiments, linkergroup is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—,—CCl═CH—, —CH═CCl—, or —C≡C—.

The R⁶ group of R¹ is C(R^(f))₃ in some embodiments, wherein one R^(f)is R^(e), wherein R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and eachother R^(f) independently is R^(a), wherein R^(a) is C₁₋₄aliphatic andpreferably each other R^(f) is R^(a) wherein R^(a) is independently foreach occurrence C₁₋₄alkyl. In particular embodiments, each other R^(f)is R^(a) wherein R^(a) is methyl or CD₃. In yet some additionalembodiments, R⁶ is —C(R^(f))₃ wherein each R^(f) is R^(a) wherein R^(a)is methyl or H or wherein each R^(f) is R^(a) wherein R^(a) is methyl orR^(b) wherein R^(b) is —C(O)OR^(c). In some additional embodiments, oneR^(f) is R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and the other twoR^(f) groups join together to provide a alicyclic (e.g., cyclopropane,cyclobutane, cyclopentane, or cyclohexane) or heterocyclic group (e.g.,epoxide, oxetane, tetrahydrofuran, tetrahydropyran, orhexahydrofuro[3,2-b]furan) with the carbon atom to which they are bound.In some such embodiments, the alicyclic and/or heterocyclic group can besubstituted, with some particular embodiments being substituted with oneor more hydroxyl groups or benzyl-carbonyl groups.

Some compound embodiments have a linker group that is a C₂_4 group,which can comprise an alkyne. In particular embodiments, R¹ is a-linker-R⁶ group and the linker is R^(a) wherein R^(a) is —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—, or —C≡C—, or —CH₂C≡C—,and R is R wherein R is —C(O)OEt or is —C(O)NR^(d)R^(d) or —NR^(d)R^(d)wherein each R independently for each occurrence is hydrogen,C₅₋₁₀heteroaryl, C₃₋₆cycloalkyl, or both R^(d) groups join together toprovide a heterocyclic group with the nitrogen atom to which they arebound, which may further comprise one or more additional heteroatomsaside from the nitrogen atom to which the R groups are bound. In someembodiments, one R^(d) is hydrogen and the other R^(d) isC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e), suchas one of the following:

R⁶ also can be R wherein R is heterocyclyl, such as pyridinyl, which canbe substituted or unsubstituted. In yet additional embodiments, R⁶ canbe R^(b) wherein R^(b) is —OH or —OR^(c)(wherein R^(c) is C₁₋₆alkyl andin some embodiments the C₁₋₆alkyl is substituted with C₅₋₁₀ heteroaryl,such as pyridinyl; or wherein R^(e) is C₅₋₁₀heteroaryl, such asquinolinyl), or R can be —NR^(d)R^(d) wherein R^(a) is independently foreach occurrence H, C₅₋₁₀heteroaryl (and in some embodiments, theC₅₋₁₀heteroaryl group is substituted with one or more R^(e) groups), ortwo R^(a) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic (and in some embodiments, the C₃₋₉heterocyclic issubstituted with one or more R groups) or a C₅₋₁₀heteroaryl (and in someembodiments, the C₅₋₁₀heteroaryl is substituted with one or more R^(e)groups). In embodiments with R^(e) substitution, R^(e) independently foreach occurrence C₅₋₁₀heteroaryl, or —OR^(a), wherein R^(a) isC₁₋₁₀alkyl.

Some compounds comprise a linker that is a C₁ group and an R⁶ group thatis R^(b), wherein R^(b) is —NR^(d)R^(d) wherein one R^(a) is H and theother R^(a) is pyridinyl, or wherein both R^(d) groups together with thenitrogen bound thereto provide a C₅₋₁₀heteroaryl; or R^(b) is OR^(c),wherein R^(c) is C₁₋₄alkyl substituted with a pyridinyl group. In someembodiments, R^(b) is

In some embodiments, R¹ can be selected from any of the following:

In some embodiments, each of R² and R³ independently is R^(a) whereinR^(a) is independently in each occurrence hydrogen, methyl, ethyl,propyl, butyl, pentyl, or hexyl. In particular embodiments, each of R²and R³ independently is R which is independently for each occurrencehydrogen, methyl, or ethyl. In exemplary embodiments, R² is methyl andR³ is hydrogen.

In some embodiments, each R⁴ independently and/or each R⁵ independentlyis R^(e), wherein R^(e) is alkyl, alkenyl, alkynyl, chloro, bromo, iodo,or fluoro. In particular embodiments, each R⁴ and/or each R⁵independently is R^(e) wherein R^(e) is lower aliphatic (e.g., methyl),fluoro, or chloro.

In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. Inparticular embodiments, m is 1, n is 0 and p is 0, 1, or 2.

The compounds of Formulas I or IA can also have structures satisfyingany one or more of Formulas II and IIA-IIF.

With reference to Formulas II and IIA-IIE, each of R¹ and R⁵ are asrecited above for Formulas I and/or IA. In particular embodiments, 0, 1,or 2 R⁵ groups are present. R⁵ can be R^(e), particularly where R^(e) isfluoro or chloro. In other particular embodiments, R⁵ is not present.With reference to Formulas IIA-IIE, each W independently is nitrogen oroxygen, and particularly nitrogen.

Certain disclosed embodiments have a Formula IIF.

With reference to Formula IIF, R¹, R² and R³ are as stated above. R¹⁰ isalkyl, cyclic alkyl or aryl. More particularly R¹⁰ is lower alkyl, suchas C₁₋₁₀ alkyl, more particularly C₁₋₅ alkyl, including methyl, ethyl,propyl, butyl and pentyl. Cyclic alkyl groups are typically selectedfrom cyclobutyl, cyclopentyl, or cyclohexyl, particularly cyclobutyl orcyclopentyl. In some embodiments, compounds according to the presentdisclosure have a Formula IIG.

For many of the disclosed embodiments, R¹⁰ is phenyl. Accordingly,certain disclosed embodiments of the present disclosure have a FormulaIIH.

With reference to Formulas IIG an IIH, each of R¹ and R⁵ are as recitedabove for Formulas I and/or IA. R⁵ may be R^(e). In particularembodiments, 0, 1, or 2 R⁵ groups are present. In certain embodiments,R⁵ is not present or is halogen, such as fluoro or chloro, particularlyfluoro, or C₁₋₆ alkyl, such as methyl.

In some embodiments, the compounds of Formulas I or IA also can havestructures satisfying any one or more of Formulas III-VI:

With reference to Formulas III-VI, each R⁵ independently can be asrecited above and in some particular embodiments is lower aliphatic(e.g., methyl) or halogen, such as chloro or fluoro. Also, ring B is asrecited above and in some embodiments may be selected from

R⁶ as illustrated in Formulas III-VI is as recited above and in someembodiments is selected from one of the following:

Certain disclosed exemplary compounds within the scope of one or more ofFormulas I, I-1 to I-35, IA, II, IIA-IIJ, and III-VI include:

Exemplary compounds within the scope of one or more of Formulas I, I-1to I-32, IA, II, IIA-IIH, and III-VI include:

-   I-1: Ethyl    (S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-2:    (S)—N-(7-(3-((1H-indazol-5-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-3:    (S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-4:    (S)-5-benzyl-N-(7-(3-((6,7-dimethoxyquinazolin-4-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-5: Ethyl    (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-6:    (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic    acid;-   I-7:    (S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-8: Ethyl    (S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;-   I-9:    (S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoic    acid;-   I-10:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-11:    (S)-5-benzyl-N-(5-methyl-7-(3-morpholino-3-oxopropyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-12:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(quinolin-7-ylamino)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-13:    (S)-5-benzyl-N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-14:    (S)-5-benzyl-N-(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-15:    (S)-5-benzyl-N-(7-(4-hydroxybutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-16:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(pyridin-2-ylmethoxy)butyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-17:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(pyridin-2-ylamino)butyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-18:    (S)-1-(2,6-dichlorobenzyl)-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-19:    (S)—N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-20:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-21:    (S)-1-(2,6-dichlorobenzyl)-N-(5-methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-22:    (S,E)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-23:    (S,E)-5-benzyl-N-(7-(3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-24:    (S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-25:    (S)-1-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-26:    (S)-1-benzyl-N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-27:    (S)—N-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-28:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbutyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-29:    (S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-30:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-31:    (S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-32:    (S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide;-   I-33:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-34:    (S)-5-(2,4-difluorobenzyl)-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-35:    (S)-5-benzyl-N-(7-(5-hydroxypent-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-36:    (S)-5-benzyl-3-((7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide;-   I-37:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-38:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-39:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-40:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-41:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-42:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-43:    (S)-5-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-44:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-45:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-46:    (S)-1-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-47:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-48:    (S)-1-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-49:    (S)-5-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-50:    (S)-1-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-51:    (S)-5-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-52:    (S)-1-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-53:    (S)-5-benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-54:    (S)-1-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-55:    (S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-56:    (S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-57:    (S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-58:    (S)-1-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-59:    (S)-5-benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-60:    (S)-5-benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-61:    (S)-5-benzyl-N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-62:    (S)-1-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-63:    (S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-64:    (S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-65:    (S)-5-(2,6-dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-66:    (S)-5-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-67:    (S)-1-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-68:    (S)—N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-69:    (S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-yn-1-yl-4,4,4-d3)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-70:    (R)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-71:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;-   I-72:    (S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-73:    (S)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-74:    (3S,3aR,6R,6aS)-6-(((S)-3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl    benzoate;-   I-75:    5-benzyl-N—((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-b]furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-76: methyl    (S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate;-   I-77:    (S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;-   I-78:    (S)-5-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-79:    (S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-80:    (S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-81:    (S)-5-benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-82:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-83:    (S)-1-([1,1′-biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-84:    (S)-1-(2,6-dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-85:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazole-3-carboxamide;-   I-86:    (S)-5-benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-87:    (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;-   I-88:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-89:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-90:    (S)-1-(2,6-dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-91:    (S)-5-benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-92:    (S)—N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;-   I-93:    (S)-5-benzyl-N-(7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-94:    (S,Z)-5-benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-95:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-96:    (S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-97:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-drobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-98:    (S)—N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-99:    (S)—N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-100:    (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-101:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide;-   I-102:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2-fluorophenoxy)picolinamide;-   I-103:    (S)-4-(2-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-104:    (S)-4-(2,4-difluorophenoxy)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-105:    (S)-4-(2,4-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-106:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide;-   I-107:    (S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-108:    (S)—N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-109:    (S)—N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-110:    (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-111:    (S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-112:    (S)-4-(2-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-113:    (R)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-114:    (S)-4-(2,4-difluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-115:    (S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-116:    (S)—N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-117:    (S)—N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide:-   I-118:    (S)-4-(2,6-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-119:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-methyl-4-phenoxypicolinamide;-   I-120:    (S)—N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-121:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-122:    (S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-123:    (S)—N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-124:    (S)-4-(2,6-dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-125:    (S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-126:    (S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-127:    (S)—N-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-128:    (S)—N-(7-((3-methoxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-129:    (S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-130:    (S)-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl    (3-morpholinopropyl)carbamate;-   I-131:    (S)—N-(7-((4-hydroxy-1-(4-phenoxypicolinoyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-132:    (S)—N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-133:    (S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-134:    (S)—N-(7-((1-acetyl-4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide;-   I-135:    (S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-136:    (S)—N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-137:    (S)—N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-138:    (S)-4-(4-fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylenepent-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-139:    (S)—N-(7-(3-amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-140:    (S)—N-(7-(3,3-dimethyl-4-morpholinobut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-141: tert-butyl    ((S)-1-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-1-oxopropan-2-yl)-12-azanecarboxylate;-   I-142:    2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl    L-alaninate;-   I-143:    (S)—N-(7-((3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-144:    (S)-4-((2,2-dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-4-oxobutanoic    acid;-   I-145:    (2R,3R)-2,3-diacetoxy-4-((2,2-dimethyl-4-((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl)oxy)-4-oxobutanoic    acid;-   I-146:    (S)—N-(7-((3-fluoro-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-147:    (R)-4-((3-((5-methyl-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoic    acid;-   I-148:    (S)-4-(4-fluorophenoxy)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-149:    (S)—N-(7-((3-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-150:    (S)—N-(7-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-151:    (S)—N-(7-((3-hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-152:    (S)-4-cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-153:    (S)-4-cyclobutoxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-154:    (S)—N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-155:    (S)—N-(7-((3-methoxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-156:    (S)-4-(cyclopentyloxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-157:    (S)-4-(cyclopentyloxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   I-158:    (S)—N-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide:-   I-159: methyl    (S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolate;-   I-160:    3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl    L-valinate;-   I-161:    (S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolic    acid;-   I-162:    (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-methoxypicolinamide;-   I-163:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-methoxypicolinamide;-   I-164:    3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl    L-valinate benzene sulfonic acid salt;-   I-165:    (S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoic    acid tris salt;-   I-166:    (S)—N-(7-((3-fluoro-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-167:    (S)—N-(7-(3-amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide    hydrochloride;-   I-168:    (S)—N-(7-((3-fluoro-1-(2,2,2-trifluoroethyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-169:    (S)—N-(7-((1-(cyclopropylmethyl)-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-170:    (S)-4-((4-(3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)oxy)-4-oxobutanoic    acid;-   I-171:    4-((S)-3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl    L-alaninate;-   I-172:    4-((S)-3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl    L-valinate;-   I-173:    (S)-2,2-dimethyl-4-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)but-3-yn-1-yl    dihydrogen phosphate;-   I-174:    (S)-4-(3-(4-(4-fluorophenoxy)picolinamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl    dihydrogen phosphate.-   I-175:    (S)-4-(4-fluorobenzyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-177:    (S)—N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide-   I-178:    (S)-4-(4-fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-179:    (S)-1-benzyl-4-fluoro-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;-   I-180:    (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-181:    (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;-   I-182:    (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;-   I-183:    (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-184:    (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-187:    (S)-5-benzyl-N-(7-(3-chloro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-188:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-189:    (S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-190:    (S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(phenoxy-d5)picolinamide;-   I-191:    (S)—N-(7-((1-acetyl-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-194:    3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl    L-alaninate trifluoroacetic acid salt;-   I-195:    (S)—N-(7-((3-hydroxy-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-196:    (S)—N-(7-((1-(cyclopropylmethyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-197:    (S)—N-(7-((1-acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-198:    (S)—N-(7-((1-(ethylcarbamoyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-199:    (S)-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl    ethylcarbamate;-   I-200:    (S)—N-(7-((3-hydroxy-1-neopentylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-203:    (S)—N-(5-methyl-7-((1-methyl-1H-imidazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-204:    (S)—N-(7-(3-(butylamino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-205:    (S)—N-(7-(3-((4-fluorobenzyl)amino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-206:    (S)—N-(5-methyl-7-(3-methyl-3-morpholinobut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-207:    (S)—N-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-208:    (S)—N-(7-((3-hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-209:    (S)—N-(7-((3-hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-210:    (S)—N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-211:    (S)—N-(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   I-212:    (S)-4-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-213:    (S)-4-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-214:    (S)-4-benzyl-N-(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-215:    (S)-4-benzyl-N-(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-216:    (S)-4-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-217:    (S)-4-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-218:    (S)-4-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-219:    (S)-4-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-220:    (S)-4-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide;-   I-221:    (S)-4-(4-fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-222:    (S)-4-(4-fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-223:    (S)-3-(4-fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-224:    (S)-4-(4-fluorobenzyl)-N-(7-((2-hydroxyspiro[3.3]heptan-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-225:    (S)-4-(4-fluorobenzyl)-N-(7-((6-hydroxy-2-oxaspiro[3.3]heptan-6-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-226:    (S)—N-(7-(3-amino-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide;-   I-227:    (S)-4-(4-fluorobenzyl)-N-(5-methyl-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-228:    (S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-229:    (S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide;-   I-230:    (S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide;-   I-231: (S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b];    [1,4]oxazepin-3-yl)-3-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide;-   I-232:    (S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide;-   I-233:    (S)-5-benzyl-N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-234:    (S)-5-benzyl-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;-   I-235:    (S)—N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide;-   I-236:    (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;-   I-237:    (S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamide;-   I-238:    (S)-4-(2,4-Difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-239:    (S)-4-(2,4-Difluorobenzyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;-   I-240: Tert-butyl    (S)-(4-(3-(4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)carbamate;-   I-241:    (S)—N-(7-(4-Amino-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamide    hydrochloride;-   II-16:    (S)—N-(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-17:    (S)-4-(4-cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   II-18:    (S)-4-(4-cyanophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   II-19:    (S)-4-(4-cyanophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   II-20:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenylpicolinamide;-   II-21:    (S)-4-(3-cyanophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide;-   II-22:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-methoxyphenyl)picolinamide;-   II-23:    (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-methoxyphenyl)picolinamide;-   II-24:    (S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-25:    (S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-26:    (S)—N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-27:    (S)—N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-28:    (S)—N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-31:    (S)—N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-32:    (S)—N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-33:    (S)—N-(7-((6-cyanopyridin-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-35:    (S)—N-(7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;-   II-36:    (S)—N-(7-(3-(dimethylamino)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;    or-   II-39:    N-((3S)-5-methyl-4-oxo-7-(pyrrolidin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide.

In some embodiments, one or more of the compounds can be included in apharmaceutical composition or medicament, and in some embodiments thecompound or compounds can be in the form of the parent compound or apharmaceutically acceptable salt, a stereoisomer, an N-oxide, atautomer, a hydrate, a solvate, an isotope, or a prodrug thereof. Thepharmaceutical composition typically includes at least one additionalcomponent other than a disclosed compound or compounds, such as apharmaceutically acceptable excipient, an adjuvant, an additionaltherapeutic agent (described in the following section), or anycombination thereof.

Pharmaceutically acceptable excipients can be included in pharmaceuticalcompositions for a variety of purposes, such as to dilute apharmaceutical composition for delivery to a subject, to facilitateprocessing of the formulation, to provide advantageous materialproperties to the formulation, to facilitate dispersion from a deliverydevice, to stabilize the formulation (e.g., antioxidants or buffers), toprovide a pleasant or palatable taste or consistency to the formulation,or the like. The pharmaceutically acceptable excipient(s) may include apharmaceutically acceptable carrier(s). Exemplary excipients include,but are not limited to: mono-, di-, and polysaccharides, sugar alcoholsand other polyols, such as, lactose, glucose, raffinose, melezitose,lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate andcitrate buffers; anti-adherents, such as magnesium stearate; binders,such as saccharides (including disaccharides, such as sucrose andlactose), polysaccharides (such as starches, cellulose, microcrystallinecellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin,synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols);coatings (such as cellulose ethers, including hydroxypropylmethylcellulose, shellac, corn protein zein, and gelatin); release aids (suchas enteric coatings); disintegrants (such as crospovidone, crosslinkedsodium carboxymethyl cellulose, and sodium starch glycolate); fillers(such as dibasic calcium phosphate, vegetable fats and oils, lactose,sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesiumstearate); flavors and sweeteners (such as mint, cherry, anise, peach,apricot or licorice, raspberry, and vanilla; lubricants (such asminerals, exemplified by talc or silica, fats, exemplified by vegetablestearin, magnesium stearate or stearic acid); preservatives (such asantioxidants exemplified by vitamin A, vitamin E, vitamin C, retinylpalmitate, and selenium, amino acids, exemplified by cysteine andmethionine, citric acid and sodium citrate, parabens, exemplified bymethyl paraben and propyl paraben); colorants; compression aids;emulsifying agents; encapsulation agents; gums; granulation agents; andcombinations thereof.

B. Combinations of Therapeutic Agents

The compounds described herein may be used alone, in combination withone another, in separate pharmaceutical compositions, together in asingle pharmaceutical composition, or as an adjunct to, or incombination with, other established therapies. The compound or compoundsor composition comprising the compound (or compounds) may beadministered once, or in plural administrations. In some embodiments,the compounds of the present disclosure may be used in combination withother therapeutic agents useful for the disorder or condition beingtreated. These other therapeutic agents may be administeredsimultaneously, sequentially in any order, by the same route ofadministration, or by a different route as the presently disclosedcompounds. For sequential administration, the compound(s) and thetherapeutic agent(s) may be administered such that an effective timeperiod of at least one compound and the therapeutic agent overlaps withan effective time period of at least one other compound and/ortherapeutic agent. In an exemplary embodiment of a combinationcomprising four components, the effective time period of the firstcomponent administered may overlap with the effective time periods ofthe second, third and fourth components, but the effective time periodsof the second, third and fourth components independently may or may notoverlap with one another. In another exemplary embodiment of acombination comprising four components, the effective time period of thefirst component administered overlaps with the effective time period ofthe second component, but not that of the third or fourth; the effectivetime period of the second component overlaps with those of the first andthird components; and the effective time period of the fourth componentoverlaps with that of the third component only. In some embodiments, theeffective time periods of all compounds and/or therapeutic agentsoverlap with each other.

In some embodiments, the compounds are administered with anothertherapeutic agent, such as an analgesic, an antibiotic, ananticoagulant, an antibody, an anti-inflammatory agent, animmunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with anti-canceror cytotoxic agents. Various classes of anti-cancer and anti-neoplasticcompounds include, but are not limited to, alkylating agents,antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, such as azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrimidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhbitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and

MPDL3280A/RG7446. Additional checkpoint inhibitors for combination withthe compounds disclosed herein include, Anti-LAG-3 agents, such asBMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513).

The presently disclosed compounds also may be used advantageously withCAR-T therapies. Example of currently available CAR-T therapies areaxicabtagene ciloleucel and tisagenlecleucel.

Additional anti-proliferative compounds useful in combination with thecompounds of the present disclosure include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent compounds include proteasome inhibitors, such as bortezomib,carfilzomib, marizomib and the like.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude: Btk inhibitors, such as ibrutinib; CDK inhibitors, such aspalbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib; Mek inhibitors, such astrametinib; Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib; FLT-3 inhibitors, such as gilteritinib and quizartinib,PI3-kinase inhibitors, such as idelalisib, Syk inhibitors, such asfostamatinib; and JAK inhibitors, such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected fromany of the following:

analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine,acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine,flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g.,ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides (e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies-anti-TNF-α antibodies, e.g., infliximab (Remicade™),adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants-warfarin (Coumadin™), acenocoumarol, phenprocoumon,atromentin, phenindione, heparin, fondaparinux, idraparinux,rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam,dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidalanti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine,mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors(COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac,famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen,indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone,naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants-mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues, forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

III. Methods of Making Compounds

Disclosed embodiments of the present compounds can be prepared by anysuitable method as will be understood by a person of ordinary skill inthe art. One exemplary suitable method is provided below with referenceto specific compounds in the examples, and can include the followingfirst reaction step according to Scheme 1.

With reference to Scheme 1, protected amine precursor 100 can be coupledwith R¹ group 102, which comprises an “R⁶-linker” group as illustratedin Scheme 1, using a metal-mediated, cross-coupling reaction to providethe cross-coupled product 104. In some embodiments, the metal-mediated,cross-coupling reaction can be carried out using a transition metalcatalyst, such as a palladium catalyst. Exemplary palladium catalystsinclude, but are not limited to, Pd(0) catalysts (e.g., Pd₂(dba)₃,Pd(dba)₂, Pd(PPh₃)₄, and the like) or Pd(II) catalyst (e.g., XPhos Pdgeneration 2 or generation 3, PdCl₂, Pd(OAc)₂, and the like). In someembodiments, the palladium catalyst can be used in combination withanother co-catalyst, such as CuI, to promote the cross-couplingreaction, such as in a Sonogoshira reaction. The metal-mediated,cross-coupling also can comprise using a base, such as an amine base(e.g., Et₃N), or an inorganic base (e.g., Cs₂CO₃, Na₂CO₃, K₂CO₃ or thelike), and a solvent (e.g., dimethylformamide). With reference to Scheme1, X is a suitable group for metal-mediated, cross-coupling, such as ahalogen or a triflate group and PG is an amine protecting group, whichcan be selected from, but is not limited to, a9-fluorenylmethoxycarbonyl (“Fmoc”) group, a t-butyloxycarbonyl (“Boc”)group, a trityl (“Tr”) group, an allyloxycarbonyl (“Alloc”) group, abenzyloxycarbonyl (“Cbz”) group, and the like.

Representative examples of the method steps shown in Scheme 1 areprovided below in Schemes 2A-2F. A method similar to that illustrated inScheme 2A can be used to make compounds I-14 to I-17 and I-35 byreplacing the propargylic alcohol in Scheme 2A with the correspondingalkyne group that gives rise to each of compounds I-14 to I-17 and I-35;the further modifications that can be used to arrive at the finalstructure of compounds I-14 to I-17 are discussed below.

Once cross-coupled product 104 is made, it can be subjected to anoptional linker group reduction step wherein linker groups comprisingone or more sites of unsaturation can be reduced to saturated linkergroups and/or linker groups having fewer degrees of unsaturation. If alinker reduction group is used, it can then be followed by adeprotection step and then an amide formation step, as illustrated inScheme 3. Alternatively, if a linker group reduction step is not used,then cross-coupled product 104 can be deprotected and converted to amidecompound 302.

With reference to Scheme 3, an optional linker reduction step can becarried out. For example, if the linker comprises a site of unsaturation(e.g., a double or triple bond), the site of unsaturation can be reducedsuch that it becomes fully saturated (e.g., such as reducing a doublebond and/or a triple bond to a single bond) or that it has few degreesof unsaturation (e.g., such as reducing a triple bond to a double bond).Suitable reagents for carrying out such an optional linker reductionstep are recognized by those of ordinary skill in the art with thebenefit of the present disclosure; however, one exemplary set ofconditions includes exposing cross-coupled product 104 to H₂ in thepresence of Pd on carbon. As these steps are optional, they need not becarried out in all embodiments. Instead, in some embodiments,cross-coupled product 104 can be deprotected to provide an amine that isthen converted to amide compound 302 by reacting the amine with asuitable acid coupling partner 300, as illustrated in Scheme 3.

Representative examples of the method steps shown in Scheme 3 areprovided below in Schemes 4A-4M. A method similar to that described inScheme 4A can be used to make compounds I-14 to I-17. Compounds I-16 andI-17 can be further functionalized as discussed below.

In some embodiments, the method can further comprise making one or moreadditional modifications to amide compound 302 to provide amide compound500, such as modifying an R⁶ group to form a different R⁶ group, asillustrated in Scheme 5.

With reference to Scheme 5, one or more modifications to the R⁶ groupcan be carried out. For example, if R⁶ is an ester group, it can beconverted to a carboxylic acid or to a primary alcohol. Suitablereagents for carrying out such an optional modification step arerecognized by those of ordinary skill in the art with the benefit of thepresent disclosure; however, one exemplary set of conditions includesexposing an R⁶ ester group to LiOH to provide the corresponding acid,such as is illustrated in Schemes 6A-6E below. The resulting acid caneven be further modified to provide an amide-containing product by usingsuitable amide coupling conditions (such as those described above) incombination with an amine coupling partner, such as is illustrated inSchemes 6A-6E. Similar methods can be used to make compounds I-10, I-11,I-13, I-18, I-19, I-26, I-27, I-33, I-34, and I-22 and I-23 (wherein thedouble bond of the linker group is not first reduced prior to coupling).In yet additional embodiments, compounds I-16 and I-17 can be made byconverting the terminal alcohol obtained in the above-described methodsinto a functionalized alcohol, such as for compound I-16, or to anamine, such as for compound I-17.

A number of the exemplary disclosed compounds are alkynyl substitutedanalogs. These compounds can be made using a metal-mediated couplingstrategy as discussed above with reference to Scheme 1. Scheme 7illustrates a more detailed general method for making alkynylsubstituted analogs according to the present disclosure, including, butnot limited to Example 21 and 22

With reference to Scheme 7, nitrogen was bubbled through a stirringsolution of an arylhalide (1 equivalent), compound 700, CuI (0.1-0.2equivalent), and Pd(PPh₃)₄ (0.05-0.1 equivalent) in dry DMF (3-4mL/mmol) for 3 minutes in a vial. Subsequently, to the dark reactionsolution was added NEt₃ (10 equivalents), followed by the correspondingalkyne (1.5-3 equivalents), compound 702, in quick succession. Nitrogenwas bubbled through the reaction mixture for 2 minutes, and the vialcapped. The reaction mixture was stirred at an effective reactiontemperatures, such as 70-90° C., for an effective reaction period, suchas 3-6 hours. Alternatively, the reaction mixture can be heated in amicrowave reactor (30-45 minutes) until the arylhalide 700 was consumed.The dark reaction solution was processed by one of the followingmethods: a) a work-up of diluting with ice-water/organic solvent; b)concentrated to dryness, followed by a work-up after diluting withice-water/organic solvent; or c) the crude residue was diluted withice-water, sonicated and the slurry allowed to warm to room temperature.The resulting grey/dark solid was collected by filtration, suctiondried, dissolved in THF (20 mL), filtered through Celite®/silica gelpad, and the pad was washed with THF. Subsequently, the crude materialwas purified by reverse phase column chromatographic or by normal phasesilica gel flash column chromatography to provide corresponding thealkynyl substituted analogs (Yield: 25-69%), compounds 704.

IV. Methods of Using Compounds

A. Diseases/Disorders

The disclosed compounds, as well as combinations and/or pharmaceuticalcompositions thereof, may be used to inhibit a RIP1 kinase by contactingthe kinase either in vivo or ex vivo, with a compound or compounds ofthe present disclosure, or a composition comprising a compound orcompounds of the present disclosure. Disclosed compound or compounds, orcompositions comprising a disclosed compound or compounds also can beused to ameliorate, treat or prevent a variety of diseases and/ordisorders. In particular embodiments, the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, may be useful for treating conditions in which inhibition ofRIP1 or a pathway involving RIP1 is therapeutically useful. In someembodiments, the compounds directly inhibit RIP1 kinase activity. Incertain embodiments, disclosed compounds are useful for treatingauto-immune diseases, inflammatory disorders, cardiovascular diseases,nerve disorders, neurodegenerative disorders, allergic disorders,respiratory diseases, kidney diseases, cancers, ischemic conditions,erythrocyte deficiencies, lung and brain injuries (e.g., induced byischemia-reperfusion or cisplatin and/or cerebrovascular accident), andbacterial and viral infections.

In some embodiments, the disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treator prevent allergic diseases, amyotrophic lateral sclerosis (ALS),spinal muscular atrophy, systemic lupus erythematosus, rheumatoidarthritis, type I diabetes mellitus, inflammatory bowel disease, biliarycirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunemyositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy,or asthma.

The disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, may also be useful for treatingimmune regulatory disorders related to bone marrow or organ transplantrejection or graft-versus-host disease. Examples of inflammatory andimmune regulatory disorders that can be treated with the compounds (orpharmaceutical compositions or combinations thereof) include, but arenot limited to, transplantation of organs or tissue, graft-versus-hostdiseases brought about by transplantation, autoimmune syndromesincluding rheumatoid arthritis, systemic lupus erythematosus,Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis,systemic inflammatory response syndrome, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,ischemia-reperfusion injuries, inflammatory bowel diseases, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn'sdisease, ulcerative colitis, migraine, rhinitis, eczema, interstitialnephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabeticnephropathy, multiple myositis, Guillain-Barre syndrome, Meniere'sdisease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis or myocardial infarction, scleroderma (includingsystemic scleroderma), anti-phospholipid syndrome, Wegener's granuloma,Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, corneal alkali burn, dermatitis erythema multiforme, linearIgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis,sepsis, pancreatitis, diseases caused by environmental pollution, aging,carcinogenesis, metastasis of carcinoma and hypobaropathy, diseasecaused by histamine or leukotriene-C4 release, Behcet's disease,autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis,partial liver resection, acute liver necrosis, necrosis caused by toxin,viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-Bhepatitis, cirrhosis, alcoholic liver disease, including alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity,hepatotoxicity, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, chronic kidneydiseases, kidney damage/injury (caused by, for example, nephritis, renaltransplant, surgery, administration of nephrotoxic drugs, acute kidneyinjury), augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, Parkinson'sdisease, trauma, or chronic bacterial infection.

In certain embodiments the present compounds are useful for treatingnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the compounds are useful for treatinginterleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, lysosomal storage diseases (e.g.,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sachs disease, andWolman disease).

In certain embodiments, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, are usefulfor treating and/or preventing rheumatoid arthritis, psoriaticarthritis, osteoarthritis, systemic lupus erythematosus, lupusnephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis,multiple sclerosis, psoriasis, in particular pustular psoriasis, type Idiabetes, type II diabetes, inflammatory bowel disease (Crohn's diseaseand ulcerative colitis), hyperimmunoglobulinemia d and periodic feversyndrome, cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, systemic juvenile idiopathic arthritis, adult's onset Still'sdisease, gout, gout flares, pseudogout, sapho syndrome, Castleman'sdisease, sepsis, stroke, atherosclerosis, celiac disease, DIRA(deficiency of Il-1 receptor antagonist), Alzheimer's disease,Huntington's disease, or Parkinson's disease.

Use of the present compounds in combination with other therapies isparticularly useful in treating hyperproliferative disorders. Thepresent compounds can be used to treat disorders such as cancers,leukemias and lymphomas in combination with the standard of care. By wayof example, myelodysplastic syndrome (MDS) can be treated with acompound disclosed herein along with the standard of care. Therapeuticsfor use in combination with the present compounds includehypomethylating agents, such as azacitidine and decitabine, and otherchemotherapeutic agents, such as cytarabine, daunorubicin andidarubicin. Immunomodulatory therapies, such as lenalidomide and CAR-Ttherapies, also can be used in combination with the present compoundsfor treating MDS.

Proliferative diseases that may be treated by the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, include benign or malignant tumors, solid tumor, carcinoma ofthe brain, kidney, liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin,bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiplemyeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, such as Hodgkins andNon-Hodgkins lymphoma, a mammary carcinoma, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,IL-1 driven disorders, hematopoietic neoplasms, such as the lymphomasmentioned above, MyD88 driven disorder (such as ABC diffuse large B-celllymphoma (DLBCL) and Waldenström's macroglobulinemia), Hodgkin'slymphoma, primary cutaneous T-cell lymphoma or chronic lymphocyticleukemia), smoldering or indolent multiple myeloma, or hematologicalmalignancies (including leukemia, acute myeloid leukemia (AML), DLBCL,ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocyticlymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemiavera, Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenicmarginal zone lymphoma, multiple myeloma, plasmacytoma, intravascularlarge B-cell lymphoma). In particular, the presently disclosed compoundsare useful in treating drug resistant malignancies, such as thoseresistant to JAK inhibitors, ibrutinib resistant malignancies, includingibrutinib resistant hematological malignancies, such as ibrutinibresistant CLL and ibrutinib resistant Waldenström's macroglobulinemia.

Examples of allergic disorders that may be treated using the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, include, but are not limited to, asthma (e.g.atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma,non-atopic asthma, bronchial asthma, non-allergic asthma, essentialasthma, true asthma, intrinsic asthma caused by pathophysiologicdisturbances, essential asthma of unknown or unapparent cause,emphysematous asthma, exercise-induced asthma, emotion-induced asthma,extrinsic asthma caused by environmental factors, cold air inducedasthma, occupational asthma, infective asthma caused by or associatedwith bacterial, fungal, protozoal, or viral infection, incipient asthma,wheezy infant syndrome, bronchiolitis, cough variant asthma ordrug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA),allergic rhinitis, perennial allergic rhinitis, perennial rhinitis,vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis,acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoidsinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treat,ameliorate or prevent any one, several or all of these symptoms of RA.Thus, in the context of RA, the compounds are considered to providetherapeutic benefit when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

In one embodiment, the presently disclosed compounds can be used to slowthe onset of the consequences of aging. For example, the presentcompounds reduce the heightened chronic inflammation associated withadvanced age (“inflammaging”). Myriad symptoms and conditions areassociated with inflammaging, by way of example, such conditions thatcan be treated with the present compounds include, neurodegenerativedisorders, such as Parkinson's and Alzheimer's, hematopoietic neoplasmsand myeloproliferative disorders. Additional conditions that can betreated or ameliorated by the present compounds include those describedby Franceschi C, Campisi J. Chronic inflammation (inflammaging) and itspotential contribution to age-associated diseases. J Gerontol A Biol SciMed Sci. 2014; 69 Suppl 1:S4-S9. In another aspect, the presentcompounds can be used to reduce aging effects on the reproductivesystem. For example, necroptosis induced by RIP1 signaling has beenimplicated in the aging of reproductive organs by Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019)26:11, thus the present compounds could be used to treat symptoms ofassociated with aging, such as reduced testosterone levels, reducedfertility and prostate hyperplasia.

Additional diseases or disorders that can be treated and/or preventedusing compounds and compositions of the present invention includeamyotrophic lateral sclerosis (ALS), an autoimmune syndrome, rheumatoidarthritis, type I diabetes mellitus, inflammatory bowel diseases,including Crohn's disease and ulcerative colitis, biliary cirrhosis,multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, allergic rhinitis, spondyloarthritis, ankylosingspondylitis, autoimmune hepatitis, autoimmune hepatobiliary diseases,cerebrovascular accident, allergic diseases, chronic obstructivepulmonary disease, pulmonary emphysema, Friedreich's ataxia, Lewy bodydisease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahrdisease, Menke's disease, Wilson's disease, prion disorder, destructivebone disorders such as bone resorption disease, multiple myeloma-relatedbone disorder; benign tumor, proliferative disorders, inflammatory andhyperproliferative skin disorders, an epidermal hyperproliferation,psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis,seborrhoeic dermatitis, pustular psoriasis, bullous dermatitis,dermatitis erythema multiforme, linear IgA bullous dermatitis, cementdermatitis, gingivitis, periodontitis, lesions of gingiva, alveolarbone, substantia ossea dentis, sepsis, pancreatitis, lichen planus,pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, adiposis,eosinophilic fascitis, acne, alopecia areata, male pattern alopecia,alopecia senilis, keratoconjunctivitis, vernal conjunctivitis, cornealalkali burn, Behcet's disease, uveitis associated with Behcet's disease,keratitis, herpetic keratitis, conical cornea, dystrophia epithelialiscorneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis,Vogt-Koyanagi-Harada syndrome, hematological disorders, hematologicalmalignancies, lymphomas, Hodgkins lymphoma, non-Hodgkins lymphoma,mammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, ABC diffuse large B-celllymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneousT-cell lymphoma, smoldering or indolent multiple myeloma, leukemia,acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL),chronic lymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS),myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginalzone lymphoma, multiple myeloma, plasmacytoma, intravascular largeB-cell lymphoma, IL-1 driven disorders, MyD88 driven disorders, drugresistant malignancies, such as JAK inhibitor-resistant malignancies andibrutinib resistant malignancies, for example ibrutinib resistanthematological malignancies, ibrutinib resistant CLL and ibrutinibresistant Waldenström's macroglobulinemia, acute myelogenous leukemia,chronic myelogenous leukemia; angiogenic disorders such as angiogenicdisorders including solid tumors, ocular neovascularization,hemangiomas, such as infantile hemangiomas; sepsis, septic shock,shigellosis; migraine, bronchitis, gastric ulcers, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis,interleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, a lysosomal storage disease,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sachs disease,Wolman disease, Huntington's disease, Parkinson's disease,neurodegenerative diseases, Huntington's disease, Parkinson's disease,metastatic melanoma, neurodegeneration associated with HIV infection andCMV retinitis, such as associated neurocognitive disorders or dementia,fibrotic conditions such as, nonalcoholic steatohepatitis and cardiacconditions such as, ischemia reperfusion; allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease,autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graftversus host disease, inflammatory reaction induced by endotoxin,tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter'ssyndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease;diseases characterized by massive neutrophil infiltration; rheumatoidspondylitis, gouty arthritis, psoriatic arthritis, and other arthriticconditions, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, fibroid lung, idiopathic interstitialpneumonia, allograft rejection, bone marrow rejection, fever andmyalgias due to infection, keloid formation, scar tissue formation,pyresis, influenza, chronic myelogenous leukemia; angiogenic disordersincluding solid tumors; viral diseases including acute hepatitisinfection (including hepatitis A, hepatitis B and hepatitis C), AIDS,ARC or malignancy, herpes; stroke, myocardial infarction,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardial ischemia, ischemia in stroke heart attacks, organhypoxia, vascular hyperplasia, cardiac and renal reperfusion injury,ischemia-reperfusion injury of organs which occurs upon preservation,transplantation or ischemic disease, cardiac hypertrophy,thrombin-induced platelet aggregation, endotoxemia and/or toxic shocksyndrome, conditions associated with prostaglandin endoperoxidasesyndase-2, pemphigus vulgaris, autoimmune/multiple myositis,dermatomyositis, leukoderma vulgaris, photoallergic sensitivity,ischemia reperfusion injury, cardiac ischemia reperfusion injury arisingfrom myocardial infarction, multiple system atrophy, Parkinson-plussyndromes, frontotemporal dementia, intracranial hemorrhage, cerebralhemorrhage, progressive muscular atrophy, pseudobulbar palsy,progressive bulbar palsy, spinal muscular atrophy, inherited muscularatrophy, peripheral neuropathies, progressive supranuclear palsy,corticobasal degeneration, demyelinating diseases, systemic onsetjuvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupuserythematosus (SLE), Sjögren's syndrome, anti-phospholipid syndrome(APS), primary sclerosing cholangitis (PSC), renal transplant, surgery,acute kidney injury (AKI), systemic inflammatory response syndrome(SIRS), cytokine release syndrome (CRS), acute respiratory distresssyndrome (ARDS), ARDS resulting from COVID-19, postinfectious autoimmunediseases, rheumatic fever, post-infectious glomerulonephritis, systemicsclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonarydisease (COPD), NEMO-deficiency syndrome (F-kappa-B essential modulatorgene (also known as IKK gamma or IKKG) deficiency syndrome), solid organmalignancies, lysosomal storage diseases, glaucoma, retinal degenerativedisease, retinal ischemia/reperfusion injury, renal ischemia reperfusioninjury, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, anthrax lethal toxin induced septic shock, cell death inducedby LPS, infectious encephalopathy, encephalitis, allergicencephalomyelitis, autoimmune uveoretinitis, giant cell arteritis,regional enteritis, granulomatous enteritis, distal ileitis, regionalileitis, terminal ileitis, insulin-dependent diabetes mellitus,scleroderma, systemic scleroderma, macular edema, diabetic retinopathy,central areolar choroidal dystrophy, BEST disease, adult vitelliformdisease, pattern dystrophy, myopic degeneration, central serousretinopathy, Stargardt's disease, Cone-Rod dystrophy, North Carolinadystrophy, infectious retinitis, inflammatory retinitis, uveitis,posterior uveitis, toxic retinitis and light-induced toxicity, macularedema, central areolar choroidal dystrophy, BEST disease, adultvitelliform disease, pattern dystrophy, optic nerve injury, opticneuritis, optic neuropathies, central retinal artery occlusion, ischemicoptic neuropathy (e.g., arteritic or non-arteritic anterior ischemicneuropathy and posterior ischemic optic neuropathy), compressive opticneuropathy, infiltrative optic neuropathy, traumatic optic neuropathy,mitochondrial optic neuropathy (e.g., Leber's optic neuropathy),nutritional optic neuropathy, toxic optic neuropathy and hereditaryoptic neuropathy, Dominant Optic Atrophy, Behr's syndrome,Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditaryspastic paresis, subarachnoid hemorrhage, perinatal brain injury,subclinical brain injury, spinal cord injury, anoxic-ischemic braininjury, cerebral ischemia, focal cerebral ischemia, global cerebralischemia, and hypoxic hypoxia, peritoneal damage caused by peritonealdialysis fluid (PDF) and PD-related side effects, glomerular diseases,tubulointerstitial diseases, interstitial nephritis, obstruction,polycystic kidney disease), focal glomerulosclerosis, immune complexnephropathy, diabetic nephropathy, Goodpasture's syndrome,hepatocellular cancer, pancreatic cancer, urological cancer, bladdercancer, colorectal cancer, colon cancer, breast cancer, prostate cancer,prostate hyperplasia, renal cancer, kidney carcinoma, liver carcinoma,adrenal gland carcinoma, thyroid cancer, gall bladder cancer, peritonealcancer, ovarian cancer, cervical cancer, gastric cancer, endometrialcancer, esophageal cancer, stomach cancer, head and neck cancer,neuroendocrine cancer, CNS cancer, brain tumors (e.g., carcinoma of thebrain, glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, soft tissuesarcoma, retinoblastomas, neuroblastomas, peritoneal effusions,malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblasticneoplasms, epithelial neoplasia, stomach carcinoma, carcinoma of theovaries, rectum carcinoma, prostate carcinoma, carcinoma of thepancreas, lung carcinoma, carcinoma of the vagina, carcinoma of thecervix, carcinoma of the testis, carcinoma of the genitourinary tract,carcinoma of the esophagus, carcinoma of the larynx, carcinoma of theskin, carcinoma of the bone, carcinoma of the thyroid, sarcoma,glioblastomas, neuroblastomas, gastrointestinal cancer, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, colon carcinoma,colorectal adenoma, hemangiopericytomas, myxoid carcinoma, round cellcarcinoma, squamous cell carcinomas, esophageal squamous cellcarcinomas, oral carcinomas, vulval cancer, cancers of the adrenalcortex, ACTH producing tumors, and leukemia, respiratory infectiousviruses, such as influenza virus, rhinovirus, corona virus,parainfluenza virus, RS virus, adeno virus, reo virus and the like),herpes zoster caused by herpes virus, diarrhea caused by rotavirus,viral hepatitis, AIDS, bacterial infectious diseases, such as Bacilluscereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli,Staphylococcus aureus, MRS A, Salmonella, Botulinus, Candida, Paget'sdisease, achondroplasia, osteochodrytis, hyperparathyroidism,osteogenesis imperfecta, partial liver resection, acute liver necrosis,necrosis caused by toxin, necrosis caused by viral hepatitis, necrosiscaused by shock, necrosis caused by anoxia, B-virus hepatitis,non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), acetaminophen toxicity, hepatotoxicity, hepatic failure,fulminant hepatic failure, late-onset hepatic failure,“acute-on-chronic” liver failure, chronic kidney diseases, kidneydamage/injury, kidney damage/injury caused by nephritis, kidneydamage/injury caused by renal transplant, kidney damage/injury caused bysurgery, kidney damage/injury caused by administration of nephrotoxicdrugs, augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, trauma,chronic bacterial infection, diseases caused by environmental pollution,aging, hypobaropathy, disease caused by histamine or leukotriene-C4release, muscular dystrophy, pyoderma and Sezary's syndrome, Addison'sdisease, pseudomembranous colitis, colitis caused by drug or radiation,ischemic acute renal insufficiency, chronic renal insufficiency,toxinosis caused by lung-oxygen or drugs, congenital hypophosphatasia,fibromatous lesions, fibrous displasia, bone turnover, osteolytic bonedisease, treating post-traumatic bone surgery, treating post-prostheticjoint surgery, treating post-plastic bone surgery, treating post-dentalsurgery, bone chemotherapy treatment or bone radiotherapy treatment,bone cancer, fragile plaque, disorder, occlusive disorder, stenosis,coronary artery disorders, peripheral arterial disorders, arterialocclusion, aneurysm formation, post-traumatic aneurysm formation,restenosis, post-operative graft occlusion, Guillain-Barre syndrome,Meniere's disease, polyneuritis, multiple neuritis, mononeuritis,radiculopathy, hyperthyroidism, Basedow's disease, autoimmune idiopathicthrombocytopenic purpura (autoimmune ITP), membranous nephritis,autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis,cold and warm agglutinin diseases, Evan's syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmunehemolytic anemia, agranulocytosis, pernicious anemia, megaloblasticanemia, anerythroplasia, and combinations thereof.

For particular embodiments, at least one compound, or a compositioncomprising at least one compound, according to the present invention isadministered to a subject having, or potentially developing, atopicdermatitis. In another particular embodiment, at least one compound, ora composition comprising at least one compound, according to the presentinvention is administered to a subject having, or potentiallydeveloping, rheumatoid arthritis. In another particular embodiment, atleast one compound, or a composition comprising at least one compound,according to the present invention is administered to a subject having,or potentially developing, ankylosing spondylitis. In another particularembodiment, at least one compound, or a composition comprising at leastone compound, according to the present invention is administered to asubject having, or potentially developing, myelodysplastic syndrome.

B. Formulations and Administration

Pharmaceutical compositions comprising one or more active compounds ofthe disclosure may be manufactured by any suitable method, such asmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilization processes. Thepharmaceutical compositions may be formulated using one or morephysiologically acceptable excipients (e.g., diluents, carriers, orauxiliaries), one or more adjuvants, or combinations thereof to providepreparations which can be used pharmaceutically.

The active compound(s) may be formulated in the pharmaceuticalcompositions per se, or in the form of a pharmaceutically acceptablesalt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, anisotope, or a prodrug thereof. Typically, such salts are more soluble inaqueous solutions than the corresponding free acids and bases, but saltshaving lower solubility than the corresponding free acids and bases mayalso be formed.

Pharmaceutical compositions of the disclosure may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceuticallyacceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate,isotope, or prodrug may be formulated as solutions, gels, ointments,creams, suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thepharmaceutical compositions may also contain formulating agents, such assuspending, stabilizing and/or dispersing agent. The formulations forinjection may be presented in unit dosage form, e.g., in ampules or inmultidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable excipients such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound, as is well known.

For buccal administration, the pharmaceutical compositions may take theform of tablets or lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), pharmaceutically acceptable salt,stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrugcan be conveniently delivered in the form of an aerosol spray frompressurized packs or a nebulizer with the use of a suitable propellant,e.g.) dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound (0.5 20 mg/ml);benzalkonium chloride (0.1 0.2 mg/mL); polysorbate 80 (TWEEN® 80; 0.5 5mg/ml); carboxymethylcellulose sodium or microcrystalline cellulose (115 mg/ml); phenylethanol (1 4 mg/ml); and dextrose (20 50 mg/ml). The pHof the final suspension can be adjusted to range from about pH 5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mL of thedisclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mMcitrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as asolution, emulsion, suspension, etc. suitable for administration to theeye. A variety of vehicles suitable for administering compounds to theeye are known in the art. Specific non-limiting examples are describedin U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445;5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851,which are incorporated herein by reference.

For prolonged delivery, the active compound(s) can be formulated as adepot preparation for administration by implantation or intramuscularinjection. The active ingredient maybe formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s). Certain organicsolvents, such as dimethylsulfoxide (DMSO), may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

Several approaches exist for transporting molecules across the bloodbrain barrier. These include, but are not limited to physical methods,lipid-based methods, and receptor and channel-based methods. Physicalmethods of transporting a compound across the blood-brain barrierinclude, but are not limited to, circumventing the blood-brain barrierentirely, and/or creating openings in the blood-brain barrier.Circumvention methods include, but are not limited to, direct injection(e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002),interstitial infusion/convection enhanced delivery (Bobo et al., Proc.Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994), and implanting a deliverydevice in the brain (see, e.g., Gill et al., Nature Med. 9:589-595,2003. Openings in the blood-brain barrier include, but are not limitedto, ultrasound, osmotic pressure (e.g., by administration of hypertonicmannitol and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416). Compounds also may be encapsulated in liposomes that arecoupled to antibody binding fragments that bind to receptors on thevascular endothelium of the blood-brain barrier.

For certain embodiments, the compounds can be administered continuouslyby infusion into the fluid reservoirs of the CNS or by bolus injection.Compounds can be administered using an indwelling catheter and acontinuous administration means such as a pump, or by Implantation of asustained-release vehicle. For example, the compounds may be injectedthrough chronically implanted cannulas or chronically infused with thehelp of osmotic minipumps. Subcutaneous pumps can deliver compounds tothe cerebral ventricles.

C. Dosages

The disclosed compound, pharmaceutical compositions, or combinations ofdisclosed compounds will generally be used in an amount effective toachieve the intended result, for example, in an amount effective toinhibit a RIP1 kinase and/or to treat, prevent or ameliorate aparticular condition. The disclosed compound(s), or pharmaceuticalcompositions thereof, can be administered therapeutically to achievetherapeutic benefit or prophylactically to achieve a prophylacticbenefit. Therapeutic benefit means eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

As known by those of ordinary skill in the art, the preferred dosage ofdisclosed compounds may depend on various factors, including the age,weight, general health, and severity of the condition of the patient orsubject being treated. Dosage also may need to be tailored to the sex ofthe individual and/or the lung capacity of the individual, whenadministered by inhalation. Dosage may also be tailored to individualssuffering from more than one condition or those individuals who haveadditional conditions that affect lung capacity and the ability tobreathe normally, for example, emphysema, bronchitis, pneumonia,respiratory distress syndrome, chronic obstructive pulmonary disease,and respiratory infections. Dosage, and frequency of administration ofthe disclosed compound(s) or pharmaceutical compositions thereof, willalso depend on whether the disclosed compound(s) are formulated fortreatment of acute episodes of a condition or for the prophylactictreatment of a disorder. A person of ordinary skill in the art will beable to determine the optimal dose for a particular individual.

For prophylactic administration, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient or subject at risk of developing one of thepreviously described conditions. For example, if it is unknown whether apatient or subject is allergic to a particular drug, the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can be administered prior to administration of thedrug to avoid or ameliorate an allergic response to the drug.Alternatively, prophylactic administration can be used to avoid orameliorate the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a disclosed compound(s), orpharmaceutical composition thereof, can be administered to an allergysufferer prior to expected exposure to the allergen. A disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can also be administered prophylactically tohealthy individuals who are repeatedly exposed to agents known to one ofthe above-described maladies to prevent the onset of the disorder. Forexample, a disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, can be administered to a healthyindividual who is repeatedly exposed to an allergen known to induceallergies, such as latex, in an effort to prevent the individual fromdeveloping an allergy. Alternatively, a disclosed compound, combinationsof disclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 μM, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM,from greater than 0 to 0.1 μM, or from greater than 0 to 0.05 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21 Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

In some embodiments, assays suitable for determining RIP1 activity canbe used. Such assay methods can be used to evaluate the efficacy ofcompound embodiments disclosed herein and/or that can be used todetermine amounts/dosages of the compound embodiments that can provide adesired efficacy. In some embodiments, the assay can be an ADP-Glo™assay that assesses the ability of a compound embodiment to inhibitRIP1. In other embodiments, whole cell assays using mouse and/or humancells, such as U937 and/or L929 cell necroptosis assays, can beperformed to determine safe and effective doses of compounds that can beused in human in vivo studies. Using these whole cell assays, thecompound's activity against human and/or murine RIP1 can be assessed inan in vitro context, which then allows a person of ordinary skill in theart to determine safe and effective dosages for in vivo use. Yet anotherassay that can be used to evaluate the activity of compound embodimentsdescribed herein to treat a disease or condition involving RIP1 is anacute hypothermia mouse model, which assesses the compound's ability toinhibit TNF-alpha induced hypothermia. Each of these assays, and variousresults from using these assays, are described in detail in the Examplessection of the present disclosure.

Dosage amounts of disclosed compounds will typically be in the range offrom greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or 0.001mg/kg/day or 0.01 mg/kg/day, up to at least about 100 mg/kg/day. Moretypically, the dosage (or effective amount) may range from about 0.0025mg/kg to about 1 mg/kg administered at least once per day, such as from0.01 mg/kg to about 0.5 mg/kg or from about 0.05 mg/kg to about 0.15mg/kg. The total daily dosage typically ranges from about 0.1 mg/kg toabout 5 mg/kg or to about 20 mg/kg per day, such as from 0.5 mg/kg toabout 10 mg/kg per day or from about 0.7 mg/kg per day to about 2.5mg/kg/day. Dosage amounts can be higher or lower depending upon, amongother factors, the activity of the disclosed compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the disclosed compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Pharmaceutical compositions comprising one or more of the disclosedcompounds typically comprise from greater than 0 up to 99% of thedisclosed compound, or compounds, and/or other therapeutic agent bytotal weight percent. More typically, pharmaceutical compositionscomprising one or more of the disclosed compounds comprise from about 1to about 20 total weight percent of the disclosed compound and othertherapeutic agent, and from about 80 to about 99 weight percent of apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition can further comprise an adjuvant.

Preferably, the disclosed compound, combinations of disclosed compounds,or pharmaceutical compositions thereof, will provide therapeutic orprophylactic benefit without causing substantial toxicity. Toxicity ofthe disclosed compound can be determined using standard pharmaceuticalprocedures. The dose ratio between toxic and therapeutic (orprophylactic) effect is the therapeutic index. Disclosed compounds thatexhibit high therapeutic indices are preferred.

V. EXAMPLES Example 1

Compounds of the present disclosure can be made using a suitablestarting compound, such as compound 200 or compound 206, illustrated inthe schemes above. A representative method for making compound 200 isillustrated in Scheme 8A and a representative method for making compound206 is illustrated in Scheme 8B.

Spectral characterization for3-(S)—N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200)

¹H nmr (400 MHz, CDCl₃) δ 7.41-7.38 (6H, m, 6H of C(C₆H₅)₃), 7.25-7.15(10H, m, oxobenzoxazapineH-8, 9H of C(C₆H₅)₃), 7.00 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.37 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.53 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH₃).

Characterization data and particular methods of making representativecompounds disclosed herein are provided below.

Example 2

Synthesis of(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

A mixture of the bromooxazapine (0.210 g, 0.410 mmol, 1.0 eq) potassiumcarbonate (0.566 g, 4.101 mmol, 10.0 eq) and copper(I) iodide (0.008 g,0.041 mmol, 0.1 eq) in dimethylformamide (3.0 mL) was degassed bybubbling argon through for five minutes. 2-Methyl-2-hydroxybut-3-yne(0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq) andtetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 eq)were added and the reaction sealed before heating in the microwave to120° C. for 1 hour. The reaction was partitioned between EtOAc (80 mL)and water (80 mL). The organics were washed with brine (80 mL), water(80 mL) and brine (80 mL), dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (10→80% EtOAc-hexane) yielded the starting material(0.091 g) and the title compound (0.079 g) as a colorless oil; ¹H nmr(400 MHz, CDCl₃) δ 7.40-7.38 (6H, m, 6H of C(C₆H₅)₃), 7.24-7.7.14 (9H,m, 9H of C(C₆H₅)₃), 7.13 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8),6.96 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 6.95 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.55 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 2.78 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂); m/z:555 [M+K]⁺, 243 [C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group

To a solution of the trityl protected amine (0.079 g, 0.153 g, 1.0 eq)in dioxane (2.0 mL) was added a solution of hydrogen chloride (0.15 mLof a 4M solution in dioxane, 0.614 mmol, 4.0 eq). The reaction wasstirred at room temperature for 6 hours before concentrating to drynessto obtain a white solid, which was used without purification; m/z: 275[M+H]⁺.

Synthesis of(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of the aminooxobenzoxazapine hydrochloride (0.076 mmol,1.0 eq) and benzyltriazole carboxylic acid (0.017 g, 0.084 mmol, 1.1 eq)in dimethylformamide (1.0 mL) was added diisopropylamine (0.025 g, 0.033mL, 0.190 mmol, 2.5 eq) followed by HATU (0.032 g, 0.084 mmol, 1.1 eq).The reaction was stirred at room temperature for 4 hours and partitionedbetween EtOAc—CH₂Cl₂ (5:1, 60 mL) and NaHCO₃(60 mL). The organics werewashed with brine (50 mL), water (50 mL) and brine (50 mL), dried(Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10%MeOH—CH₂Cl₂) yielded the title compound as a white solid; ¹H nmr (400MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.22 (7H, m, 7×ArH), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CCH ₂C₆H₅), 3.40 (3H, s, NCH₃), 1.63(6H, s, C(CH ₃)₂OH); m/z: 442 [M+H−H₂O]⁺.

Similar steps as those above for Example 2 can be used to make compoundsI-14, to I-17, and I-35.

Example 3

Synthesis of ethyl(S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylate

To a suspension of tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(0.500 g, 1.35 mmol, 1.0 eq) in dimethylformamide (8 mL) was degassed bybubbling argon through for five minutes. Ethyl acrylate (0.270 g, 0.29mL, 2.70 mmol, 2.0 eq) and triethylamine (0.272 g, 0.37 mL, 2.0 eq) wereadded followed by tetrakis(triphenylphosphine (0.156 g, 0.14 mmol, 0.1eq). The reaction was sealed and heated in the microwave to 100° C. for1 hour and 120° C. for 1 hour. The reaction was partitioned betweenEtOAc (100 mL) and water (100 mL). The organics were washed with brine(70 mL), water (100 mL) and brine (70 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (10→40%EtOAc-hexane) yielded the title compound (0.250 g, %) as a yellow foam;¹H nmr (400 MHz, CDCl₃) δ 7.62 (1H, d, J 16.0 Hz, ArCH═CHCO), 7.35 (1H,dd, J 8.0, 2.0 Hz, oxobenzoxazepineH-8), 7.33 (1H, d, J 2.0 Hz,oxobenzoxazepineH-6), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepineH-9), 6.37(1H, d, J 16.0 Hz, ArCH═CHCO), 5.49 (1H, d, J 7.0 Hz, NH), 4.65 (1H, dt,J 11.0, 7.0 Hz, oxobenzoxazepineH-3), 4.57 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.27 (2H, q, J 7.0 Hz, OCH ₂CH₃), 4.19 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepineH-2), 3.41 (3H, s, NCH₃), 1.39 (9H,s, C(CH₃)₃), 1.34 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z: 291 [M+H—CO₂—C₄H₈]⁺.

Synthesis of ethyl(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

A solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq) inethyl acetate (20 mL) was added palladium on carbon (0.23 g). Thereaction was purged with hydrogen and stirred under an atmosphere ofhydrogen for 14 hours. The reaction was purged with nitrogen andfiltered through Celite®, eluting with ethyl acetate (2×20 mL). Thefiltrate was concentrated under reduced pressure; ¹H nmr (400 MHz,CDCl₃) δ 7.04-6.82 (3H, m, oxobenzoxazepineH-6, H-8, H-9), 5.50 (1H, d,J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.52(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.14-4.07 (1H, m, 1Hof oxobenzoxazepineH-2), 4.12 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.36 (3H, s,NCH₃), 2.91 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 2.59 (2H, t, J 7.5 Hz,2H of ArCH₂CH₂CO), 1.37 (9H, s, C(CH₃)₃), 1.23 (3H, t, J 7.0 Hz,OCH₂CH₃); m/z: 337 [M+H—C₄H₈]⁺, 293 [M+H—CO₂—C₄H₈]⁺. The crude materialwas dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL ofa 4M solution in dioxane, 3.21 mmol, 5.0 eq). The reaction was stirredat room temperature for 14 hours before adding further hydrogen chloridesolution (0.8 mL, 5.0 eq). After stirring for a further 2 hours thereaction was concentrated under reduced pressure and dried under vacuumto obtain a brown solid. The crude material was used without furtherpurification; m/z: 293 [M+H]⁺.

Synthesis of ethyl(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq) was added to asolution of the ethyl(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate(0.140 g, 0.477 mmol, 1.0 eq) and diisopropylethylamine (0.154 g, 0.21mmol, 2.5 eq) in dimethylformamide (5.0 eq). HATU (0.199 g, 0.525 mmol,1.1 eq) was added and the reaction stirred at 0° C. for 1 hour and roomtemperature for 1 hour. The reaction was partitioned between EtOAc (120mL) and NaHCO₃ water (1:1, 120 mL). The organics were washed with brine(100 mL), water (100 mL) and brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (40→80%EtOAc-hexane) yielded the title compound 0.138 mg) as a white solid; ¹Hnmr (400 MHz, CDCl₃) δ 8.11 (1H, s, triazoleH-5), 8.05 (1H, d, 7.0 Hz,NH), 7.38-7.30 (2H, m, 2H of C₆H₄F), 7.26-7.07 (6H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-7, H-8, H-9), 5.42 (2H, s, CH ₂C₆H₄F), 5.08 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); ¹³C nmr (100 MHz, CDCl₃) δ168.9, 160.6 (d, J 248.5 Hz), 158.3, 156.7, 150.1, 144.1 (d, J 2.0 Hz),136.0, 131.1 (d, J 8.5 Hz), 130.9 (d, J 2.5 Hz), 127.6, 125.7, 124.9 (d,J Hz), 123.3, 123.1, 121.2 (d, J 14.0 Hz), 115.8 (d, J 21.5 Hz), 77.3,49.2, 47.9 (d, J 4.0 Hz), 35.5; ¹⁹F nmr (380 MHz, CDCl₃) δ−118.1; m/z:518 [M+Na]⁺, 496 [M+H]⁺ (found [M+H]⁺, 496.1991, C₂₅H₂₆FN₅O₅ requires[M+H]⁺496.1973).

Similar steps as those above for Example 3 and those below for Examples4 and 5 can be used to make compounds I-10, I-11, I-13, I-18, I-19,I-26, I-27, I-33, I-34, and I-22 and I-23 (wherein the double bond ofthe linker group is not first reduced prior to coupling).

Example 4

Synthesis of(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicacid

To a solution of the ethyl ester (0.103 g, 0.208 mmol, 1.0 eq) intetrahydrofuran (3 mL) was added aqueous lithium hydroxide (0.017 g,0.416 mmol, 2.0 eq in 1 mL of water). The reaction was stirred at roomtemperature for 3 hours before partitioning between EtOAc (80 mL) andNH₄Cl (80 mL). The aqueous phase was extracted with EtOAc (2×60 mL). Thecombined organics were washed with brine (80 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (0→10%MeOH—CH₂Cl₂) yielded the title compound 0.054 g, %) was a white solid;¹H nmr (400 MHz, CDCl₃) δ 8.12 (1H, s, triazoleH-5), 8.04 (1H, d, J 7.5Hz, NH), 7.40-7.30 (2H, m, 2×ArH), 7.16 (1H, dd, J 7.5, 1.0 Hz, 1×ArH),7.14-7.10 (2H, m, 2×ArH), 7.07 (2H, m, 2×ArH), 5.43 (2H, s, NCH ₂C₆H₅F),5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.73 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazepineH-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazepineH-2), 3.41 (3H, s, NCH), 2.96 (2H, t, J 7.5 Hz, 2H ofArCH₂CH₂CO), 2.70 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO); ¹⁹F nmr (CDCl₃)δ−118.1 (dd, J 16.5, 7.0 Hz); m/z: 468 [M+H]⁺ (found [M+H]⁺, 468.1688,C₂₃H₂₂FN₅O₅ requires [M+H]⁺ 468.1678).

Example 5

Synthesis of(S)—N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A solution of(S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicacid (0.049 g, 0.105 mmol, 1.0 eq) and 6-aminoindazole (0.017 g, 0.126mmol, 1.2 eq) in dimethylformamide (10 mL) was cooled to 0° C.Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 eq) was addedfollowed by HATU (0.048 g, 0.126 mmol, 1.2 eq) and the reaction stirredat 0° C. for 1 hour and room temperature for 2 hours. The reaction waspartitioned between EtOAc (50 mL) and NaHCO₃ (50 mL). The organics werewashed with brine (50 mL). The combined aqueous phase was extracted withEtOAc (20 mL). The combined organics were washed with water (50 mL) andbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure.Column chromatography (0→10% MeOH—CH₂Cl₂) yielded the title compound(0.xx g, %) yielded the title compound as a white solid; ¹H nmr (400MHz, CDCl₃) δ 8.12 (1H, s, triazoleH-5), 8.00 (1H, d, J 7.5 Hz, NH),7.94 (1H, d, J 0.5 Hz, indazoleH-3), 7.90 (1H, s, NH), 7.83 (1H, m,indazoleH-7), 7.57 (1H, d, J 9.0 Hz, indazoleH-4), 7.37-7.30 (2H, m, 2Hof C₆H₄F), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H of C₆H₄F), 7.09-7.00 (5H, m,indazoleH-5, 1H of C₆H₄F, oxobenzoxazepineH-6, H-7, H-9), 5.40 (2H, s,NCH ₂C₆H₄F), 5.02 (1H, td, J 11.5, 7.5 Hz, oxobenzoxazepineH-3), 4.63(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.23 (1H, dd, J11.5, 9.5 Hz, 1H of oxobenzoxazepineH-2), 3.29 (3H, s, NCH₃), 3.03 (2H,t, J 7.0 Hz, ArCH ₂CH₂CON), 2.68 (2H, m, ArCH₂CH ₂CON); ¹³C nmr (CDCl₃)δ 170.6, 168.7, 160.7 (d, J 248.5 Hz), 158.8, 156.4, 148.4, 144.4,140.6, 138.5, 136.3, 135.9, 134.3, 131.2 (d, J 8.5 Hz), 131.0 (d, J 3.0Hz), 127.5, 124.9 (d, J 4.0 Hz), 123.4, 122.9, 121.1, 121.0, 120.3,115.8 (d, J 20.5 Hz), 115.3, 101.1, 77.2, 49.1, 48.0 (d, J 4.0 Hz),39.3, 35.3, 31.1; ¹⁹F nmr (CDCl₃) δ−118.0; m/z: 583 [M+H]⁺ (found[M+H]⁺, 583.2205, C₃₀H₂₇FN₈O₄ requires [M+H]⁺ 583.2212).

Example 6

Ethyl(S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.96 (1H, s,triazoleH-5), 7.42 (2H, m, 2×ArH), 7.32 (1H, dd, J 9.0, 7.0 Hz, 1×ArH),7.10 (1H, m, 1×ArH), 7.06 (2H, dd, J 6.0, 2.0 Hz, 2×ArH), 5.70 (2H, s,CH₂C₆H₃Cl₂), 5.07 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.74(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.21 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepineH-2), 4.14 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.41 (3H, s, NCH₃), 2.95 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO),2.63 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 1.24 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 172.5, 168.9, 158.3, 156.5, 148.4, 143.9,138.4, 136.9, 135.8, 131.4, 129.1, 128.9, 127.5, 123.2, 122.9, 77.2,60.6, 49.4, 49.3, 35.7, 35.5, 30.3, 14.2; m/z: 548, 546 [M+H]⁺ (found[M+H]⁺, 546.1291, C₂₅H₂₅C₁₂N₅O₅ requires [M+H]⁺546.1306).

Example 7

(S)-3-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoicacid

¹H nmr (400 MHz, CDCl₃) δ 8.13 (1H, d, J 7.5 Hz, NH), 7.32-7.22 (5H, m,5×ArH), 7.08-7.06 (3H, m, 3×ArH), 4.97 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.38 (3H, s, NCH₃), 2.94(2H, m, 2H of ArCH ₂CH ₂CO₂H), 2.70 (2H, m, 2H of ArCH ₂CH ₂CO₂H); ¹⁹Fnmr (CDCl₃) δ−118.1; m/z: 450 [M+H]⁺ (found [M+H]⁺, 450.1760, C₂₃H₂₃N₅O₅requires [M+H]⁺450.1772).

Example 8

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.29-7.21 (5H, m,5×ArH), 7.10-7.07 (3H, m, 3×ArH), 5.05 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH₂Ph), 3.45 (2H, t, J 7.0 Hz, 2H ofpyrrolidine), 3.38 (3H, s, NCH3), 3.35 (2H, m, 2H of pyrrolidine), 2.97(2H, t, J 7.5 Hz, 2H of ArCH2CH2CO), 2.57 (2H, t, J 7.5 Hz, 2H ofArCH2CH2CO), 1.92 (2H, m, 2H of pyrrolidine), 1.83 (2H, m, 2H ofpyrrolidine); ¹³C nmr (100 MHz, CDCl₃) δ 170.4, 168.9, 158.5, 148.2,139.5, 135.9, 135.7, 128.9, 128.8, 127.6, 127.1, 123.5, 122.7, 77.1.49.2, 46.6, 45.8, 36.6, 35.5, 33.2, 30.4, 26.0, 24.4; m/z: 503 [M+H]⁺(found [M+H]⁺, 503.2403, C₂₇H₃₀N₆O₄ requires [M+H]⁺503.2401).

Example 9

Synthesis of(S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylamide

To a mixture of the bromooxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq)and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) was added dimethylformamide(5 mL) and the mixture degassed by bubbling argon through for fiveminutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was addedfollowed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq) and the reactionsealed and heated to 120° C. in the microwave for 1 hour. The reactionwas partitioned between EtOAc (100 mL) and NaHCO₃ (100 mL). The organicswere washed with brine (80 mL), water (100 mL) and brine (80 mL) dried(Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10%MeOH—CH₂Cl₂) yielded the title compound (0.267 g, 91%) as a pale yellowsolid; ¹H nmr (400 MHz, CDCl₃) δ 7.55 (1H, d, J 15.5 Hz, ArCH═CHCO),7.39-7.36 (7H, m, 6H of C(C₆H₅)₃, oxobenzoxazapineH-8), 7.25-7.13 (9H,m, 9H of C(C₆H₅)₃), 7.01 (1H, d, J 8.5 Hz, oxobenzoxazepineH-9), 6.97(1H, d, J 2.0 Hz, oxobenzoxazepineH-6), 6.39 (1H, d, J 15.5 Hz,ArCH═CHCO), 5.95 (2H, br s, NH₂), 4.51 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazepineH-2), 3.54 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.31 (1H, d, J 8.5 Hz, NH), 2.94 (3H, s, NCH);m/z: 526 [M+Na]⁺, 243 [C(C₆H₅)₃]⁺.

Synthesis of(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide

A solution of the α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0eq) in ethyl acetate methanol (5:2, 7 mL) was purged with nitrogen andpalladium on carbon (0.100 g) added. The reaction was purged withhydrogen and stirred under an atmosphere of hydrogen for 2 hours. Thereaction was purged with nitrogen and filtered through celite, elutingwith EtOAc (30 mL). The filtrate was concentrated under reducedpressure. The residue was dissolved in dioxane (5 mL) and hydrogenchloride (0.66 mL of a 4M solution in dioxane, 2.659 mmol, 5.0 eq)added. The reaction was stirred at room temperature for 6 hours, a whitesolid formed. The reaction was concentrated to dryness and used withoutpurification; m/z: 265 [M+H]⁺.

Synthesis of(S)—N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide

To a mixture of the aminooxobenzoxazapine hydrochloride (0.134 mmol, 1.0eq) and the benzyltriazole carboxylic acid (0.033 g, 0.161 mmol, 1.2 eq)in dimethylformamide (1.0 mL) was added diisopropylethylamine (0.043 g,0.058 mL, 0.335 mmol, 2.5 eq) followed by HATU (0.102 g, 0.268 mmol, 2.0eq). The reaction was stirred at room temperature for 4 hours andpartitioned between EtOAc—CH₂Cl₂ (5:1, 60 mL) and water (60 mL). Theorganics were washed with brine (50 mL), water (60 mL) and brine (50mL). The organics were dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the title compound as a whitesolid; ¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.36-7.28(5H, m, 5×ArH), 7.11-7.06 (3H, m, 3×ArH), 5.44 (2H, br s, CONH₂), 5.02(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 2.99(2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 2.54 (2H, t, J 7.5 Hz, 2H ofArCH₂CH₂CO); m/z: 449 [M+H]⁺.

Example 10

Formation of(S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

Dioxane (4 mL) and water (2 mL) were added to a mixture of thebromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq),7-((trifluoro-λ⁴-boraneyl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine,potassium salt (0.180 g, 0.738 mmol, 1.4 eq) and caesium carbonate(0.515 g, 1.581 mmol, 3.0 eq). The reaction was degassed by bubblingargon through for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05eq) was added and the reaction sealed and heated in the microwave to140° C. for 45 minutes. The reaction was partitioned between EtOAc (80mL) and NaHCO₃(80 mL). The organics were washed with brine (80 mL),dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10% MeOH[2M NH3]—CH₂Cl₂) yielded the title compound (0.255 g, %) as a yellowoil; ¹H nmr (400 MHz, CDCl₃) δ 7.88 (1H, s, triazoleH-3), 7.38-7.35 (6H,m, 6H of C(C₆H₅)₃), 7.21-7.11 (9H, m, 9H of C(C₆H₅)₃), 7.02 (1H, dd, J8.0, 2.0 Hz, oxobenzoxazapineH-8), 6.97 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.36 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.16 (2H, t, J 5.5 Hz, 2H ofNCH₂CH₂N), 3.82 (2H, s, ArCH₂N or NCH₂CN), 3.69 (2H, s, ArCH₂N orNCH₂CN), 3.51 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 2.91 (2H,t, J 5.5 Hz, 2H of ArCH₂CH₂N), 2.88 (3H, s, NCH₃); m/z: 593 [M+Na]⁺, 243[C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group

To a solution of the trityl protected amine (0.255 g, 0.447 mmol, 1.0eq) in dioxazne (4.0 mL) was added hydrogen chloride (0.56 mL of a 4Msolution in dioxane, 2.237 mmol, 5.0 eq). A white precipitate formed.The reaction was stirred at room temperature for 14 hours. The reactionwas concentrated to dryness and used without purification; m/z: 329[M+H]⁺.

Formation of(S)-5-benzyl-N-(74(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of the aminooxobenzoxazapine hydrochloride (0.377 mmol,1.0 eq) and benzyltriazole carboxylic acid (0.077 g, 0.377 mmol, 1.0 eq)in dimethylformamide (4.0 mL) was added diisopropylethylamine (0.122 g,0.16 mL, 0.943 mmol, 2.5 eq). The reaction was cooled to 0° C. and HATU(0.143 g, 0.377 mmol, 1.0 eq) added. The reaction was stirred at 0° C.for 2 hours and room temperature for 18 hours. The reaction waspartitioned between EtOAc—CH₂Cl₂ (9:1, 60 mL) and NaHCO₃-water (1:1, 60mL). The organics were washed with brine (60 mL). The combined aqueousphase was back-extracted with EtOAc (30 mL). The combined organics werewashed with water (90 mL) and brine (90 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. MPLC (0→8% MeOH—CH₂Cl₂) yielded thetitle compound as a white solid; ¹H nmr (400 MHz, CDCl₃) δ 7.90 (1H, brm, NH), 7.75 (1H, s, triazoleH-3), 7.29-7.21 (7H, m, 7×ArH), 7.16 (1H,d, J 8.0 Hz, oxobenzoxazapineH-9), 5.10 (1H, oxobenzoxazapineH-3), 4.74(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, t, 10.0Hz, 1H of oxobenzoxazapineH-2), 4.21 (2H, t, J 5.5 Hz, 2H of NCH₂CH₂N),4.15 (2H, s, NCH ₂C₆H₅), 3.84, 3.78 (2H, 2d AB system, J 15.5 Hz, ArCH₂Nor NCH₂C), 3.77, 3.73 (2H, 2d AB system, J 13.5 Hz, ArCH₂N or NCH₂C),3.40 (3H, s, NCH₃), 3.02 (2H, t, J 5.5 Hz, 2H of NCH₂CH₂N); m/z: 514[M+H]⁺ (found [M+H]⁺, 514.2324, C₂₆H₂₇N₉O₃ requires [M+H]⁺514.2310).

Additional exemplary compound embodiments are described below.

(S)-5-benzyl-34(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide

¹H nmr (400 MHz, D₆DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H, d, J2.0 Hz, oxobenzoxazapineH-6), 7.25 (1H, dd, J 8.0, 2.0 Hz,oxobenzoxazapineH-8), 7.20-7.15 (5H, m, oxobenzoxazapineH-9, 4H ofC₆H₅), 7.09-7.04 (1H, m, 1H of C₆H₅), 5.47 (1H, br s, OH), 4.81-4.74(1H, m, oxobenzoxazapineH-3), 4.39-4.36 (2H, m, 2H ofoxobenzoxazapineH-2), 3.84 (2H, s, CH ₂C₆H₅), 3.28 (3H, s, NCH₃), 1.44(6H, s, C(CH ₃)₂OH); m/z: 442 [M+H]⁺.

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.76 (1H, dd, J 4.0, 1.5 Hz, quinolineH-2),8.03 (2H, m, NH, quinolineH-4), 8.01 (1H, d, J 9.5 Hz, quinolineH-8),7.99 (1H, s, triazoleH-5), 7.40 (1H, dd, J 9.0, 3.0 Hz, quinolineH-7),7.37-7.7.33 (4H, m, 4H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.28-7.24(3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 2.5 Hz,quinolineH-5), 7.10 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.36 (2H, s,NCH₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75 (1H,dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.30 (2H, t, J 7.0 Hz,CCH₂CH ₂O), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2),3.39 (3H, s, NCH₃), 2.98 (2H, t, J 7.0 Hz, CCH ₂CH₂O); m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2244, C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.73 (1H, dd, J 4.0, 1.5 Hz, quinolineH-2),8.05 (2H, m, NH, quinolineH-4), 8.00 (1H, d, J 9.5 Hz, quinolineH-8),7.40 (1H, dd, J 9.5, 3.0 Hz, quinolineH-7), 7.34 (1H, m, quinolineH-3),7.25 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.25-7.20 (6H, m,C₆H₅, oxobenzoxazapineH-7), 7.11 (1H, d, J 3.0 Hz, quinolineH-5), 7.09(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (2H, t, J 7.0 Hz, CCH₂CH ₂O), 4.26 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.14 (2H, s, CH₂C₆H₅), 3.37(3H, s, NCH₃), 2.98 (2H, t, J 7.0 Hz, CCH ₂CH₂O); ¹³C nmr (100 MHz,CDCl₃) δ 168.7, 156.6, 149.7, 148.0, 144.3, 136.0, 134.9, 131.0, 130.8,129.2, 128.8 (2C), 128.6, 127.1, 126.5, 123.1, 122.4, 121.4, 121.0,106.3, 86.6, 80.7, 77.2, 66.2, 49.1, 35.4, 33.4, 20.4; m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2262, C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.38-7.33 (3H, m, 3H of C₆H₅), 7.27-7.24 (2H, m, 2H ofC₆H₅), 7.19 (2H, m, oxobenzoxazapineH-6, H-8), 7.15 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.35 (2H, s, NCH₂C₆H₅), 5.09 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26-4.21 (3H, m, 1H of oxobenzoxazapineH-2, 2H ofNCH₂CH₂N), 3.87 (2H, s, 2H of ArCH₂NCH₂C), 3.75 (2H, s, 2H ofArCH₂NCH₂C), 3.40 (3H, s, NCH₃), 3.01 (2H, td, J 5.0, 1.5 Hz, 2H ofNCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.4, 156.6, 153.5 (q, J39.5 Hz), 152.2, 149.6, 143.9, 136.4, 134.5, 133.7, 129.2, 129.0, 128.2,127.8, 123.4, 123.3, 119.2 (q, J 270.5 Hz), 77.2, 60.6, 54.3, 50.7,49.2, 48.4, 47.1, 35.6; ¹⁹F nmr (380 MHz, CDCl₃) δ−65.4 m/z: 582 [M+H]⁺(found [M+H]⁺, 582.2188, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺ 582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27-7.21 (6H, m,C₆H₅, oxobenzoxazapineH-8), 7.21 (1H, dd, J 7.5, 2.0 Hz,oxobenzoxazapineH-8), 7.15 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.07(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.69 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.29-4.23 (3H, m, 1H ofoxobenzoxazapineH-2, 2H of NCH₂CH₂N), 4.12 (2H, s, CH ₂C₆H₅), 3.86 (2H,s, 2H of ArCH₂NCH₂C), 3.76 (2H, s, 2H of ArCH₂NCH₂C), 3.39 (3H, s,NCH₃), 3.03 (2H, t, J 5.5 Hz, 2H of NCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃)δ 168.8, 158.7, 153.4 (q, 139.5 Hz), 152.2, 149.6, 136.3, 135.7, 134.6,128.8, 128.7, 127.9, 127.1, 123.4, 123.2, 123.1, 119.2 (q, J 269.5 Hz),77.1, 60.7, 50.4, 49.4, 48.6, 47.1, 35.6, 33.0; ¹⁹F nmr (380 MHz, CDCl₃)δ−65.3 m/z: 582 [M+H]⁺ (found [M+H]⁺, 582.2167, C₂₇H₂₆F₃N₉O₃ requires[M+11]⁺582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, dd, J 4.5, 2.0 Hz, quinolineH-2),8.09-8.06 (2H, m, NH, quinolineH-4), 7.70 (1H, d, J 9.0 Hz,quinolineH-5), 7.50 (1H, d, J 2.5 Hz, quinolineH-8), 7.27-7.17 (9H, m,quinolineH-3, H-6, oxobenzoxazapineH-6, H-8, C₆H₅), 7.07 (1H, d, J 8.5Hz, oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (2H, td, J 7.0, 2.5 Hz, OCH ₂CH₂C), 4.24 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅),3.36 (3H, s, NCH₃), 2.97 (2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz,CDCl₃) δ 168.7, 159.6, 158.6, 150.3, 149.6, 149.5, 136.0 (2C), 135.9,131.0, 128.9, 128.8, 128.7, 127.0, 126.5, 123.7, 123.0, 121.0, 120.1,119.1, 107.9, 86.8, 80.6, 77.2, 66.1, 49.2, 35.5, 33.2, 20.3; m/z: 573[M+H]⁺ (found [M+H]⁺, 573.2269, C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.20 (1H, dd, J 4.5, 2.0 Hz, quinolineH-2),8.06 (1H, dd, J 8.0, 1.5 Hz, quinolineH-4), 8.03 (1H, d, J 7.0 Hz, NH),7.99 (1H, s, triazoleH-5), 7.70 (1H, d, J 9.0 Hz, quinolineH-5), 7.45(1H, d, J 2.5 Hz, quinolineH-8), 7.37-7.33 (3H, m, 3H of C₆H₅,oxobenzoxazapineH-6), 7.27-7.22 (6H, m, quinolineH-6, H-3,oxobenzoxazapineH-8, 3H of C₆H₅, oxobenzoxazapineH-6), 7.09 (1H, dd, J8.0, 0.5 Hz, oxobenzoxazapineH-9), 5.35 (2H, s, NCH ₂C₆H₅), 5.06 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.33 (2H, t, J 7.0 Hz, OCH ₂CH₂C), 4.23 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 2.98(2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 159.4,158.4, 156.6, 150.6, 149.8, 149.7, 143.9, 135.9, 135.7, 133.7, 130.9,129.2, 128.9, 128.2, 126.5, 123.7, 123.1, 121.0, 119.9, 119.1, 108.2,86.6, 80.7, 77.1, 66.1, 54.3, 49.1, 38.6, 35.5, 20.3; m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2249, C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-5-(2,4-difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.27-7.20 (3H, m,oxobenzoxazapineH-6, H-8, 1H of C₆H₃F₂), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 6.82-6.74 (2H, m, 2H of C₆H₃F₂), 4.99 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₃F₂), 3.39 (3H, s, NCH₃), 1.61(6H, s, C(CH ₃)₂OH); ¹⁹F nmr (380 MHz, CDCl₃) δ−111.2; −113.2; m/z: 478[M+H—H₂O]⁺ (found [M+H]⁺, 496.1795, C₂₅H₂₃F₂N₅O₄ requires[M+H]⁺496.1791).

(S)-1-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.89 (1H, dd, J 4.0, 2.0 Hz, quinolineH-2),8.63 (1H, ddd, J 8.5, 2.0, 1.0 Hz, quinolineH-4), 8.02 (1H, d, J 7.5 Hz,NH), 7.99 (1H, s, triazoleH-5), 7.70 (1H, d, J 8.5 Hz, quinolineH-8),7.59 (1H, dd, J 8.5, 7.5 Hz, quinolineH-7), 7.38-7.33 (4H, m,quinolineH-3, 3H of C₆H₅, oxobenzoxazapineH-6), 7.26-7.22 (4H, m,oxobenzoxazapineH-8, 3H of C₆H₅, oxobenzoxazapineH-6), 7.09 (1H, d, J8.0 Hz, oxobenzoxazapineH-9), 6.89 (1H, dd, J 7.5, 0.5 Hz,quinolineH-6), 5.35 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.73 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.35 (2H, t, J 7.0 Hz, OCH ₂CH₂C), 4.24 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.37 (3H, s, NCH₃), 3.03 (2H,t, J 7.0 Hz, OCH₂CH ₂C); m/z: 573 [M+H]⁺ (found [M+H]⁺, 573.2251,C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, dd, J 4.0, 2.0 Hz, quinolineH-2),8.64 (1H, ddd, J 8.5, 2.0, 1.0 Hz, quinolineH-4), 8.07 (1H, d, J 7.5 Hz,NH), 7.69 (1H, d, J 8.5 Hz, quinolineH-8), 7.59 (1H, dd, J 8.5, 7.5 Hz,quinolineH-3), 7.26-7.17 (7H, m, C₆H₅, oxobenzoxazapineH-6, H-8), 7.08(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 6.90 (1H, dd, J 8.0, 0.5 Hz,quinolineH-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.36 (2H, t, J 7.0Hz, OCH ₂CH₂C), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.36 (3H, s, NCH₃), 3.04(2H, t, J 7.0 Hz, OCH₂CH ₂C); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.5,153.9, 150.6, 149.7, 148.9, 136.0, 131.0, 130.9, 129.4, 128.8, 128.7,127.0, 126.5, 123.1, 121.8, 121.0, 120.9, 120.3, 105.4, 86.7, 80.7,77.2, 49.1, 35.5, 33.2, 20.5; m/z: 573 [M+H]⁺ (found [M+H]⁺, 573.2266,C₃₃H₂₈N₆O₄ requires [M+H]⁺573.2245).

(S)-1-benzyl-N-(5-methyl-4-oxo-74(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 8.02 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3×ArH), 7.29-7.7.26 (2H, m, 2×ArH), 7.20(2H, m, 2×ArH), 7.17 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.38 (2H,s, NCH₂C₆H₅), 5.12 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.26 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.15 (2H, t, J 5.5 Hz, 2H ofNCH₂CH₂N), 3.98, 3.93 (2H, 2d AB system, J 15.5 Hz, 2H of ArCH₂NCH₂),3.76 (2H, s, 2H of ArCH₂NCH₂), 3.42 (3H, s, NCH₃), 2.96 (2H, dt, J 4.0,5.5 Hz, 2H of NCH₂CH₂N); ¹⁹F nmr (380 MHz, CDCl₃) δ−63.2; m/z: 582[M+H]⁺ (found [M+H]⁺, 582.2173, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺582.2183).

(S)-5-benzyl-N-(5-methyl-4-oxo-74(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27-7.19 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.16 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.09 (1H, dt, J 10.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 10.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (4H, m, 2H of NCH₂CH₂N), 2H of ArCH₂NCH₂ orCH ₂C₆H₅), 3.93 (2H, s, 2H of ArCH₂NCH₂ or CH ₂C₆H₅), 3.78, 3.74 (2H, 2dAB system, J 13.5 Hz, 2H of ArCH₂NCH₂), 3.40 (3H, s, NCH₃), 2.97 (2H, t,J 5.5 Hz, 2H of NCH₂CH₂N); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.6,152.0, 149.6, 143.4 (q, J 40.0 Hz), 136.4, 135.8, 134.3, 128.8, 128.7,127.9, 127.1, 126.9, 123.4, 123.2, 118.3 (q, J 270.5 Hz), 77.2, 60.8,49.5, 49.4, 43.6, 35.6, 33.1; ¹⁹F nmr (380 MHz, CDCl₃) δ−63.2; m/z: 582[M+H]⁺ (found [M+H]⁺, 582.2208, C₂₇H₂₆F₃N₉O₃ requires [M+H]⁺ 582.2183).

(S)-1-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s,triazoleH-5), 7.40-7.36 (3H, m, 3H of C₆H₅), 7.29-7.23 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.38 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); m/z:458 [M+H]⁺ (found [M+H]⁺, 458.2205, C₂₆H₂₇N₅O₃ requires [M+H]⁺458.2187).

(S)-5-benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.07 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J Hz, 1H of oxobenzoxazapineH-2),4.15 (2H, s, CH₂C₆H₅), 3.40 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹³Cnmr (100 MHz, CDCl₃) δ 168.7, 158.5, 149.2, 135.9, 135.8, 130.9, 128.8,128.7, 127.0, 126.4, 122.8, 121.8, 99.4, 77.6, 77.2, 49.1, 35.5, 33.2,30.9, 27.9; m/z: 458 [M+H]⁺ (found [M+H]⁺, 458.2200, C₂₆H₂₇N₅O₃ requires[M+H]⁺458.2187).

(S)-1-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s,triazoleH-5), 7.38-7.34 (3H, m, 3H of C₆H₅), 7.29-7.25 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.36 (2H, s, NCH ₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 2.55-2.49 (2H, m, 2H ofcBuH-2, H-4), 2.33 (2H, m, 2H of cBuH-2, H-4), 1.87 (2H, m, cBuH-3);m/z: 472 [M+H]⁺, 454 [M+H—H₂O]⁺ (found [M+H]⁺, 472.1994, C₂₆H₂₅N₅O₄requires [M+H]⁺ 472.1979).

(S)-5-benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J 7.5 Hz, NH), 7.29-7.20 (7H, m,C₆H₅, 2H of oxobenzoxazapineH-6, H-8, H-9), 7.10 (1H, dd, J 7.5, 1.0 Hz,1H of oxobenzoxazapineH-6, H-8, H-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15, 4.11 (2H, 2d AB system, J 16.0 Hz, CH₂C₆H₅), 3.39 (3H, s, NCH₃), 2.57-2.50 (2H, m, 2H of cBuH-2, H-4), 2.35(2H, m, 2H of cBuH-2, H-4), 1.92-1.84 (2H, m, cBuH-3); ¹³C (100 MHz,CDCl₃) δ 168.7, 158.7, 149.9, 136.0, 135.8, 131.0, 128.8, 128.7, 127.0,126.5, 123.0, 120.4, 93.4, 81.9, 76.9, 68.2, 49.1, 38.5, 35.5, 33.0,13.0; m/z: 454 [M+H—H₂O]⁺ (found [M+H]⁺, 472.1999, C₂₆H₂₅N₅O₄ requires[M+H]⁺ 472.1979).

(S)-1-benzyl-N-(74(1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.99 (1H, s,triazoleH-5), 7.38-7.34 (3H, m, 3H of C₆H₅), 7.28-7.26 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.36 (2H, s, NCH₂C₆H₅), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 2.08-1.99 (4H, m, cPentaneH-2,H-5), 1.90-1.84 (2H, m, 2H of cPentaneH-3, H-4), 1.83-1.76 (2H, m, 2H ofcPentaneH-3, H-4); m/z: 486 [M+H]⁺, 468 [M+H—H₂O]⁺ (found [M+H]⁺,486.2122, C₂₇H₂₇N₅ 04 requires [M+H]⁺486.2136).

(S)-5-benzyl-N-(74(1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-7), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃),2.08-1.97 (4H, m, cPentaneH-2, H-5), 1.90-1.85 (2H, m, 2H ofcPentaneH-3, H-4), 1.82-1.76 (2H, m, 2H of cPentaneH-3, H-4); m/z: 468[M+H—H₂O]⁺ (found [M+H]⁺, 486.2154, C₂₇H₂₇N₅O₄ requires [M+H]⁺486.2136).

(S)-1-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.02 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3H of C₆H₅), 7.31-7.27 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-6, H-8), 7.14 (1H, dd, J 8.0, 1.0 Hz,oxobenzoxazapineH-9), 5.37 (2H, s, NCH ₂C₆H₅), 5.08 (1H, dt, J 11.5, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.95 (2H, dt, J 12.0, 4.5 Hz, 2H of pyranH-2,H-6), 3.72 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H of pyranH-2, H-6), 3.42(3H, s, NCH₃), 2.07-2.02 (2H, m, 2H of pyranH-3, H-5), 1.89 (2H, ddd, J13.0, 9.0, 4.0 Hz, 2H of pyranH-3, H-5); m/z: 502 [M+H]⁺, 484 [M+H—H₂O]⁺(found [M+H]⁺, 502.2105, C₂₇H₂₇N₅ 05 requires [M+H]⁺ 502.2085).

(S)-5-benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28-7.19 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.64 (1H, dd, J 9.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH₂C₆H₅), 3.93 (2H, dt, J 12.0, 4.5Hz, 2H of pyranH-2, H-6), 3.70 (2H, ddd, J 11.5, 9.0, 2.5 Hz, 2H ofpyranH-2, H-6), 3.37 (3H, s, NCH₃), 2.03 (2H, m, 2H of pyranH-3, H-5),1.88 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H of pyranH-3, H-5); ¹³C nmr (100MHz, CDCl₃) δ 168.6, 158.7, 150.1, 136.1, 135.7, 131.1, 128.9, 128.8,127.1, 126.6, 123.2, 120.0, 92.3, 83.4, 77.3, 66.1, 64.8, 49.1, 39.9,35.6, 33.1; m/z: 484 [M+H—H₂O]⁺ (found [M+H]⁺, 502.2080, C₂₇H₂₇N₅O₅requires [M+H]⁺502.2085).

(S)-i-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.40 (2H, m, 2H of C₆H₅),7.27-7.22 (3H, m, oxobenzoxazapineH-6, H-8, 1H of C₆H₅), 7.10 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 7.05 (2H, m, 2H of C₆H₅), 6.93 (1H, dd, J5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.70 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 1.61 (6H,s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7,151.3, 150.1, 150.0, 136.2, 130.8, 130.3, 126.4, 125.6, 123.0, 120.7,120.3, 114.4, 110.6, 94.4, 80.7, 77.2, 65.6, 49.3, 35.4, 31.4; m/z: 472[M+H]⁺ (found [M+H]⁺, 472.1891, C₂₇H₂₅N₃ 05 requires [M+H]⁺472.1867).

(S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.14 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4),4.80 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.70 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.16 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 2.98(1H, br s, OH); m/z: 474 [M+H]⁺ (found [M+H]⁺, 474.1789, C₂₅H₂₃N₅O₅requires [M+H]⁺474.1772).

(S)-1-benzyl-N-(7-(0-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s,triazoleH-5), 7.37 (3H, m, 3H of C₆H₅), 7.28-7.25 (4H, m, 2H of C₆H₅,oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9),5.35 (2H, s, NCH ₂C₆H₅), 5.04 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.89 (2H, dd, J 7.0, 1.0 Hz, 2H of oxetaneH-2,H-4), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H of oxobenzoxazapineH-2,H-4), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.26(1H, dd, J 11.5, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.53 (1H, s, OH),3.38 (3H, s, NCH₃); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.4, 156.5,150.4, 144.0, 136.1, 133.7, 130.9, 129.2, 129.0, 128.2, 126.6, 123.4,119.5, 88.9, 84.5, 77.1, 67.3, 54.4, 53.4, 49.1, 35.5; m/z: 474 [M+H]⁺.

(S)-5-benzyl-N-(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0Hz, 2H of C₆H₅), 7.20-7.15 (5H, m, 3H of C₆H₅, oxobenzoxazapineH-6,H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.41 (1H, q, J 1.0Hz, 1H of ═CH₂), 5.32 (1H, m, 1H of ═CH₂), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₅), 3.38 (3H, s, NCH₃), 1.98(3H, t, J Hz, C(CH ₃)═CH₂); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.7,154.6, 149.8, 136.0, 135.9, 130.9, 128.8, 128.7, 127.0, 126.4 (2C),123.1, 122.6, 121.0, 91.3, 86.7, 77.2, 49.2, 35.5, 33.0, 23.3; m/z: 464[M+Na]⁺, 442 [M+H]⁺ (found [M+H]⁺, 442.1869, C₂₅H₂₃N₅O₃ requires [M+H]⁺442.1874).

(S)-5-benzyl-N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.29-7.19 (5H, m,C₆H₅), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 7.03 (1H, d, J 2.0Hz, oxobenzoxazapineH-6), 7.00 (1H, m, oxobenzoxazapineH-8), 5.04 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.22 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃), 2.60(2H, m, CH ₂CH₂CH(CH₃)₂), 1.60 (1H, m, CH₂CH₂CH(CH₃)₂), 1.52-1.46 (2H,m, CH₂CH ₂CH(CH₃)₂), 0.94 (6H, d, J 6.5 Hz, CH₂CH₂CH(CH ₃)₂); m/z: 448[M+H]⁺ (found [M+H]⁺, 448.2335, C₂₅H₂₉N₅O₃ requires [M+14]⁺448.2343).

(S)-5-benzyl-N-(7-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.25 (2H, m,2H of C₆H₅), 7.19 (5H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.09(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.63 (1H, dd, J 9.0, 8.0 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 10.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (2H, s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃ orOCH₃), 3.39 (3H, s, NCH₃ or OCH₃), 1.54 (6H, s, C(CH ₃)₂OCH₃); m/z: 474[M+H]⁺, 442 [M+H—CH₃OH]⁺ (found [M+H]⁺, 474.2138, C₂₆H₂₇N₅O₄ requires[M+14]⁺474.2136).

(S)-1-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.39-7.34 (3H, m, 3H of C₆H₅), 7.27-7.23 (4H, m, 2H ofC₆H₅, oxobenzoxazapineH-8, H-9), 7.12 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 5.36 (2H, s, NCH ₂C₆H₅), 5.05 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂OH); m/z:460 [M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1968, C₂₅H₂₅N₅O₄ requires[M+H]⁺460.1979).

(S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.18 (7H, m,C₆H₅, oxobenzoxazapineH-7, H-9), 7.11 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14, 4.10 (2H, 2d, J 16.0 Hz, CH ₂C₆H₅), 3.37(3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂O H); ¹³C nmr (100 MHz, CDCl₃) δ168.7, 158.7, 149.5, 136.1, 135.9, 129.0, 128.8, 128.7, 127.0, 126.0,123.1, 122.2, 95.1, 80.6, 76.9, 65.5, 49.2, 35.4, 33.0, 31.4 (2C); m/z:442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1972, C₂₅H₂₅N₅O₄ requires[M+H]⁺460.1979).

(S)—N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.83 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyridineH-3), 7.60 (1H, d, J 2.5 Hz, pyridineH-6), 7.42-7.38 (2H, m,2H of C₆H₅), 7.28-7.22 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-7, H-9),7.13 (1H, d, J 8.0 Hz, oxobenzoxazapineH-6), 7.07-7.04 (2H, m, 2H ofC₆H₅), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyridineH-4), 5.01 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 1.61 (6H, s, C(CH ₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.6,136.4, 130.3, 128.9, 126.0, 125.7, 123.0, 122.0, 120.7, 114.4, 110.6,94.9, 80.6, 77.2, 65.6, 49.4, 35.3, 31.4; m/z: 472 [M+H]⁺ (found [M+H]⁺,472.1873, C₂₇H₂₅N₃O₅ requires [M+H]⁺472.1867).

(S)-5-(2,6-dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.33-7.29 (3H, m,3H of C₆H₃Cl₂, oxobenzoxazapineH-6), 7.226-7.24 (1H, m, 1H of C₆H₃Cl₂,oxobenzoxazapineH-6), 7.18-7.15 (1H, m, oxobenzoxazapineH-8)), 7.10 (1H,d, J 8.5 Hz, oxobenzoxazapineH-9), 5.00 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.48 (2H, s, CH ₂C₆H₃Cl₂), 4.27 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 3.39 (3H, s, NCH₃), 1.61 (6H, s,C(CH₃)₂); m/z: 532, 530, 528 [M+H]⁺514, 512, 510 [M+H—H₂O]⁺ (found[M+H]⁺, 528.1201, C₂₅H₂₃Cl₂N₅O₄ requires [M+H]⁺528.1200).

(S)-5-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30-7.17 (8H, m,C₆H₅, oxobenzoxazapineH-6, H-7, H-9), 5.08 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30-4.25 (3H, m, 1H of oxobenzoxazapineH-2,NCH₂CH₂N), 4.14 (2H, s, CH₂C₆H₅), 3.88, 3.83 (2H, 2d AB system, J 16.0Hz, 2H of ArCH₂NCH₂), 3.76 (2H, s, ArCH₂NCH₂), 3.40 (3H, s, NCH₃),3.09-3.02 (2H, m, NCH₂CH₂N); ¹⁹F nmr (380 MHz, CDCl₃) δ−65.3; m/z: 604[M+Na]⁺582 [M+H]⁺.

(S)-1-benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s,triazoleH-5), 7.39-7.35 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-7,H-9), 7.28-7.25 (2H, m, 2H of C₆H₅, oxobenzoxazapineH-6, H-7, H-9),7.23-7.17 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-7, H-9), 5.37 (2H,s, NCH ₂C₆H₅), 5.11 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28-4.23 (3H, m, 1Hof oxobenzoxazapineH-2, 2H of NCH₂CH₂N), 3.90, 3.86 (2H, 2d AB system, J16.0 Hz, 2H of ArCH₂NCH₂), 3.79, 3.75 (2H, 2d AB system, J 13.5 Hz, 2Hof ArCH₂NCH₂), 3.42 (3H, s, NCH₃), 3.10-3.02 (2H, m, 2H of NCH₂CH₂N);¹⁹F nmr (380 MHz, CDCl₃) δ−65.4; m/z: 604 [M+Na]⁺, 582 [M+H]⁺.

(S)—N-(7-(3-hydroxy-3-(methyl-d₃)but-1-yn-1-yl-4,4,4-d₃)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-3), 7.60 (1H, d, J 2.5 Hz, pyH-4), 7.42-7.38 (2H, m, 2H ofC₆H₅), 7.27-7.22 (3H, m, 3H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.10-7.05 (2H, m, 2H of C₆H₅,oxobenzoxazapineH-6, H-8), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-6), 5.01(1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃); m/z: 478 [M+H]⁺, 460[M+H—H₂O]⁺ (found [M+H]⁺, 478.2255, C₂₇H₁₉D₆N₃O₄ requires [M+H]⁺478.2244).

(S)-5-benzyl-N-(7-(3-hydroxy-3-(methyl-d₃)but-1-yn-1-yl-4,4,4-d₃)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.39 (3H, s, NCH₃); ¹³Cnmr (100 MHz, CDCl₃) δ 168.6, 158.5, 149.9, 136.0, 135.8, 131.0, 128.8(2C), 127.1 (2C), 126.5, 123.1, 120.5, 94.6, 80.6, 77.2, 65.3, 49.1,35.5, 33.2, 30.5 (m); m/z: 466 [M+H]⁺, 448 [M+H—H₂O]⁺ (found [M+H]⁺,466.2356, C₂₅H₁₉D₆N₅O₄ requires [M+H]⁺ 466.2356).

(R)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[α]₅₈₉ ^(20.2)+135.9 (CHCl₃, c 0.54); ¹H nmr (400 MHz, CDCl₃) δ 8.08(1H, d, J 7.5 Hz, NH), 7.30-7.23 (7H, m, C₆H₅, oxobenzoxazapineH-6,H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₅), 3.40 (3H, s, NCH₃), 1.63(6H, s, C(CH₃)₂OH); m/z: 460 [M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺,460.1985, C₂₅H₂₅N₅O₄ requires [M+H]⁺460.1979).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.99 (1H, d, J 6.5 Hz, NH), 7.36-7.29 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.13 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 4.97 (1H, ddd, J 11.0, 7.5, 7.0 Hz,oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, m, 1H of oxobenzoxazapineH-2), 4.26 (2H,s, CH₂C₆H₅), 3.43 (3H, s, NCH₃), 1.63 (6H, s, C(CH₃)₂); m/z: 484[M+Na]⁺, 443 [M+H—H₂O]⁺ (found [M+H]⁺, 443.1727, C₂₅H₂₄N₄O₅ requires[M+H—H₂O]⁺443.1714).

(S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.42-7.39 (2H, m, 2H ofC₆H₅), 7.31 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-7), 7.27-7.22 (2H,m, 1H of C₆H₅, oxobenzoxazapineH-9), 7.17 (1H, d, J 8.0 Hz,oxobenzoxazapineH-6), 7.07-7.05 (2H, m, 2H of C₆H₅), 6.93 (1H, dd, J5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.93 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, d, J 7.0 Hz, 2Hof oxetaneH-2, H-4), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); m/z: 486 [M+H]⁺, (found[M+H]⁺, 486.1674, C₂₃H₂₃N₃O₆ requires [M+H]⁺486.1660).

(S)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.97 (1H, s, OH),7.32-7.22 (6H, m, C₆H₅, oxobenzoxazapineH-7), 7.20 (1H, d, J 2.0 Hz,oxobenzoxazapineH-9), 7.14 (1H, d, J 8.5 Hz, 1H of oxobenzoxazapineH-6),4.99 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.92 (2H, d, J 7.0Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, d, J 6.5 Hz, 2H of oxetaneH-2,H-4), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.25 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅),3.40 (3H, s, NCH₃); m/z: 474 [M+H]⁺, 456 [M+H—H₂O]⁺ (found [M+H]⁺,474.1784, C₂₅H₂₃N₅O₅ requires [M+H]⁺ 474.1772).

(3S,3aR,6R,6aS)-6-(((S)-3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-ylbenzoate

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 8.03 (2H, m, 2H ofCOC₆H₅), 7.59 (1H, tt, J 7.5, 1.0 Hz, 1H of COC₆H₅), 7.45 (2H, t, J 7.5Hz, 2H of COC₆H₅), 7.32-7.23 (7H, m, CH₂C₆ H ₅, oxobenzoxazapineH-6,H-8), 7.12 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 5.23 (1H, d, J 3.0Hz, isosorbateH-6), 5.02 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3),4.87, 4.83 (2H, 2d AB system, J 4.5 Hz, isosorbateH-3a, H-6a), 4.69 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.25-4.20 (2H, m, isosorbateH-5),4.15 (2H, s, CH ₂C₆H₅), 4.04, 3.95 (2H, 2d AB system, J 9.5 Hz,isosorbateH-2), 3.40 (3H, s, NCH₃); m/z: 650 [M+H]⁺ (found [M+H]⁺,650.2283, C₃₅H₃₁N₅O₈ requires [M+H]⁺650.2245).

5-benzyl-N—((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-b]furan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.51 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.36 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.33-7.23 (5H, m,C₆H₅), 7.19 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.01 (1H, dd, J11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.65, 4.54 (2H, 2d AB system, J 4.5Hz, isosorbateH-3a, H-6a), 4.60 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.24 (1H, d, J 2.5 Hz, isosorbateH-6), 4.15 (2H,s, CH ₂C₆H₅), 3.99-3.91 (2H, m, 2H of isosorbateH-5), 3.93, 3.71 (2H, 2dAB system, J 8.5 Hz, isosorbateH-2), 3.40 (3H, s, NCH₃); ¹³C nmr (100MHz, CD₃OD) δ 169.1, 150.3, 136.5, 130.7, 128.4, 128.3, 126.8, 126.6,122.7, 119.9, 110.0, 89.5, 88.6, 87.1, 83.7, 78.1, 77.8, 77.5, 74.4,49.1, 34.4, 33.2; m/z: 546 [M+H]⁺ (found [M+H]⁺, 546.2007, C₂₈H₂₇N₅O₇requires [M+H]⁺546.1983).

methyl(S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-ynoate

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.10 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.16 (2H, s, CH₂C₆H₅), 3.78 (3H, s, OCH₃), 3.41(3H, s, NCH₃), 1.58 (6H, s, C(CH₃)₂); m/z: 502 [M+H]⁺ (found [M+H]⁺,502.2107, C₂₇H₂₇N₅O₄ requires [M+H]⁺502.2085).

(S)-1-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.79 (1H, d, J 7.0 Hz, NH), 7.38-7.32 (4H, m,4H or C₆H₅, pyrazoleH-4 or H-5, oxobenzoxazapineH-6, H-8), 7.28-7.21(4H, m, 4H of C₆H₅, pyrazoleH-4 or H-5, oxobenzoxazapineH-6 or H-8),7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 6.74 (1H, d, J 2.5 Hz,pyrazoleH-4 or H-5), 5.31 (2H, s, NCH ₂C₆H₅), 5.05 (1H, dt, J 11.0, 7.0Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); m/z:459 [M+H]⁺, 441 [M+H—H₂O]⁺ (found [M+H]⁺, 459.2040, C₂₆H₂₆N₄O₄ requires[M+H]⁺459.2027).

(S)-5-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m,oxobenzoxazapineH-6, H-8), 7.21 (1H, m, 1H of C₆H₄F), 7.10 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 7.01 (1H, br d, J 8.0 Hz, 1H of C₆H₄F), 6.96(1H, br d, J 9.5 Hz, 1H of C₆H₄F), 6.90 (1H, td, J 8.5, 2.5 Hz, 1H ofC₆H₄F), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66 (1H,dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₄F), 3.40 (3H,s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CD₃OD) δ 168.5,164.0, 161.6, 149.9, 138.5, 135.9, 131.0, 130.2 (d, J 8.5 Hz), 128.8,126.5, 124.5 (d, J 2.5 Hz), 123.0, 120.5, 115.8 (d, J 22.0 Hz), 113.9(d, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4; ¹⁹F nmr(380 MHz, CDCl₃) δ−112.6; m/z: 460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1901,C₂₅H₂₄FN₅O₄ requires [M+H]⁺478.1885).

(S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27-7.25 (2H, m,oxobenzoxazapineH-6, H-8), 7.17 (2H, dd, J 8.5, 5.5 Hz, 2H of C₆H₄F),7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 6.90 (2H, t, J 8.5 Hz, 2Hof C₆H₄F), 4.99 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.64 (1H,dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.29 (1H, dd, J 11.5,10.0 Hz, 1H of oxobenzoxazapineH-2), 4.09 (2H, s, CH ₂C₆H₄F), 3.39 (3H,s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹⁹F nmr (380 MHz, CDCl₃) δ−115.6;m/z: 478 [M+H]⁺460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1902, C₂₅H₂₄FN₅O₄requires [M+H]⁺478.1885).

(S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.16 (3H, m,oxobenzoxazapineH-6, H-8, 1H of C₆H₄F), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.01 (1H, td, J 7.5, 1.0 Hz, 1H of C₆H₄F),7.00-6.96 (1H, m, 1H of C₆H₄F), 5.00 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₄F), 3.38 (3H, s, NCH₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 160.7 (d, J 246.3Hz), 158.5, 149.9, 136.0, 131.0 (d, J 4.0 Hz), 131.0, 129.1, 129.0 (d, J8.5 Hz), 126.5, 126.3, 124.4 (d, J 4.0 Hz), 123.1, 120.4, 115.4 (d, J12.0 Hz), 94.6, 80.6, 76.9, 65.6, 49.1, 35.5, 31.4, 26.3; ¹⁹F nmr (380MHz, CDCl₃) δ−117.5; m/z: 460 [M+H—H₂O]⁺ (found [M+H]⁺, 478.1895,C₂₅H₂₄FN₅O₄ requires [M+H]⁺478.1885).

(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.40-7.38 (6H, m, 3×2H of C₆H₅), 7.24-7.20(6H, m, 3×2H of C₆H₅), 7.18-7.12 (4H, m, 3×1H of C₆H₅, 1H ofoxbenzoxazapineH-6, H-8, H-9), 6.97-6.95 (2H, m, 2H ofoxobenzoxazapineH-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.55 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.28 (1H, d, J 8.5 Hz, NH), 2.88 (3H, s, NCH₃),1.63 (6H, s, C(CH ₃)₂OH); m/z: 561 [M−H+HCO₂H]⁻.

(S)-5-benzyl-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33-7.31 (2H, m,oxobenzoxazapineH-8, H-9), 7.25-7.20 (5H, m, C₆H₅), 7.09 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.15 (2H, s, CH ₂C₆H₅), 3.40 (3H, s, NCH₃), 0.26(9H, s, Si(CH₃)₃); m/z: 474 [M+H]⁺ (found [M+H]⁺, 474.1981, C₂₅H₂₇N₅O₃Sirequires [M+H]⁺474.1956).

(S)-5-benzyl-N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz,oxobenzoxazapineH-8), 7.35-7.26 (6H, m, C₆H₅, oxobenzoxazapineH-6), 7.14(1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 5.04 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.17 (2H, s, CH ₂C₆H₅), 3.42 (3H, s, NCH₃), 3.12(1H, s, HCC); ¹³C nmr (100 MHz, CDCl₃) δ 168.6, 150.4, 136.1, 131.5,128.9 (2C), 127.3, 127.0, 123.3, 119.8, 82.0, 78.1, 77.2, 49.1, 35.5,33.5; m/z: 402 [M+H]⁺ (found [M+H]⁺, 402.1561, C₂₂H₁₉N₅ 03 requires[M+H]⁺402.1576).

(S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.24 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.06 (1H, d, J 8.0Hz, oxobenzoxazapineH-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.72 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3); m/z: 275 [M+H]⁺ (found [M+H]⁺, 275.1390,C₁₅H₁₈N₂O₃ requires [M+H]⁺275.1404).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.03 (1H, d, J 7.0 Hz, NH), 7.83 (1H, s,triazoleH-5), 7.32-7.21 (5H, m, 5H of C₆H₄, oxobenzoxazapineH-6), 7.16(1H, dd, J 9.0, 2.0 Hz, oxobenzoxazapineH-8), 7.12 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.37 (2H, s, NCH ₂C₆H₄CH₃), 5.07 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 2.27 (3H, s, C₆H₄CH ₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.4, 156.5,149.9, 143.8, 136.8, 136.0, 131.4, 131.1, 130.9, 129.7, 129.4, 126.8,126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 52.6, 49.1, 35.5, 31.4,19.0; m/z: 474 [M+H]⁺, 456 [M+H—H₂O]⁺

(S)-1-([1,1′-biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, s, traizoleH-5), 8.06 (1H, d, J 7.0Hz, NH), 7.60-7.55 (4H, m, 4H of C₆H₄C₆H₅), 7.45-7.42 (2H, m, 2H ofC₆H₄C₆H₅), 7.38-7.34 (3H, m, 3H of C₆H₄C₆H₅), 7.28-7.26 (2H, m,oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),5.41 (2H, s, NCH ₂C₆H₄Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 1.62 (6H, s, C(CH ₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 169.1, 158.7, 157.0, 150.3, 144.3, 142.3, 140.4,136.3, 132.9, 131.2, 129.2, 129.0, 128.2, 128.0, 127.4, 126.8, 123.5,120.7, 94.9, 80.9, 77.5, 65.9, 54.4, 49.4, 35.8, 31.7; m/z: 536 [M+H]⁺,518 [M+H—H₂O]⁺

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.59 (1H, s,triazoleH-5), 7.28-7.21 (3H, m, 3H of oxobenzoxazapineH-6, H-8, H-9, C₆H ₃(CH₃)₂), 7.13-7.10 (3H, m, 3H of oxobenzoxazapineH-6, H-8, H-9,C₆H₃(CH ₃)₂), 5.41 (2H, s, NCH ₂C₆H₃(CH₃)₂), 5.06 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 2.30 (6H, s, C₆H₃(CH ₃)₂),1.62 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.8, 158.5,156.5, 149.9, 143.1, 138.1, 136.0, 130.9, 129.6, 129.0 (2C), 126.5,123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 49.1, 49.0, 35.5, 31.4, 19.6; m/z:488 [M+H]⁺, 470 [M+H—H₂O]⁺ (found [M+H]⁺, 488.2292, C₂₇H₂₉N₅O₄ requires[M+H]⁺488.2292).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.04 (1H, s, triazoleH-5), 8.03 (1H, d, J 7.0Hz, NH), 7.29-7.26 (2H, m, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz,oxobenzoxazapineH-3), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.98 (2H, d, J 7.0 Hz, NCH ₂CH(CH₃)₂), 3.41 (3H,s, NCH₃), 2.30-2.23 (1H, m, CH(CH₃)₂), 1.62 (6H, s, C(CH ₃)₂OH), 0.91(6H, dd, J 6.5, 1.0 Hz, CH(CH ₃)₂); ¹³C nmr (100 MHz, CDCl₃) δ 168.9,158.5, 156.5, 149.9, 144.3, 136.0, 130.9, 126.5, 123.2, 120.4, 94.5,80.6, 77.1, 65.5, 57.6, 49.1, 35.5, 31.4, 29.0, 19.7; m/z: 426 [M+H]⁺,408 [M+H—H₂O]⁺ (found [M+H]⁺, 426.2126, C₂₂H₂₇N₅O₄ requires[M+H]⁺426.2136).

(S)-5-benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.30-7.18 (5H, m, 5H of C₆H₅,oxobenzoxazapineH-6, H-8, H-9), 7.13-7.06 (3H, m, 3H of C₆H₅,oxobenzoxazapineH-6, H-8, H-9), 6.85-6.77 (0.66H, m,oxobenzoxazapineH-3major), 5.34-5.27 (0.33H, m,oxobenzoxazapineH-3minor), 4.94 (0.33H, dd, J 12.0, 10.5 Hz,oxobenzoxazapineH-3minor), 4.84 (0.66H, dd, J 12.0, 9.5 Hz,oxobenzoxazapineH-3major), 4.55 (0.66H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2major), 4.50 (0.33H, m, 1H ofoxobenzoxazapineH-2minor), 4.11 (0.66H, s, CH ₂C₆H₅minor), 4.05 (1.32H,q, J 7.0 Hz, NCH ₂CH₃major), 3.91, 3.84 (1.32H, 2d AB system, J 15.5 Hz,CH ₂C₆H₅major), 3.50 (0.66H, q, J 7.0 Hz, NCH ₂CH₃minor), 3.28 (1H, s,NCH₃minor), 3.25 (2H, s, NCH₃major), 1.61 (2H, s, C(CH₃)₂OHminor), 1.57(4H, s, C(CH₃)₂OHmajor), 1.20 (3H, t, J 7.0 Hz, NCH₂CH ₃); m/z: 488[M+H]⁺, 470 [M+H—H₂O]⁺ (found [M+H]⁺, 488.2291, C₂₇H₂₉N₅O₄ requires[M+H]⁺488.2292).

(S)-5-benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m,oxobenzoxazapineH-6), 7.31 (1H, dd, J 8.0, 2.5 Hz, oxobenzoxazapineH-8),7.15 (5H, br s, C₆H₅), 7.02 (1H, dd, J 8.0, 1.0 Hz,oxobenzoxazapineH-9), 4.10 (2H, s, CH ₂C₆H₅), 3.36 (3H, s, NCH); ¹³C(100 MHz, 100 MHz) δ 168.7, 158.9, 149.1, 137.4, 135.8, 130.6, 128.8,128.7, 127.1, 126.4, 118.1, 77.2, 49.2, 35.5, 32.9; m/z: 458, 456 [M+H]⁺(found [M+H]⁺, 458.0651, C₂₀H₁₈BrN₅O₃ requires [M+H]⁺458.0645).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 7.72 (1H, d, J 7.0 Hz, NH), 7.36-7.21 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.11 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 6.30 (1H, br s, isoxazoleH-5), 4.99 (1H, dt, J11.0, 7.0 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.10 (2H, s, CH ₂C₆H₅), 3.41 (3H, s, NCH₃), 1.62(6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 174.1, 168.4, 158.5,157.9, 149.9, 136.0, 135.2, 130.9, 128.9, 128.7, 127.4, 126.5, 123.1,120.4, 101.6, 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 33.2, 31.4; m/z: 460[M+H]⁺, 442 [M+H—H₂O]⁺ (found [M+H]⁺, 460.1884, C₂₆H₂₅N₃O₅ requires[M+H]⁺460.1867).

(S)-5-benzyl-N-(5-methyl-4-oxo-74(1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.71 (1H, dd, J 5.5, 3.0 Hz, 1×ArH), 7.20 (1H,dd, J 5.5, 3.0 Hz, 1×ArH), 7.59 (1H, d, J 2.0 Hz, 1×ArH), 7.44 (1H, td,J 8.5, 2.0 Hz, 1×ArH), 7.41 (1H, br s, 1×ArH), 7.33-7.23 (6H, m, 6×ArH),5.03 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.60 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazapineH-2), 4.45 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.35 (2H, s, isoquinolineH-1), 4.16 (2H, sCH2C6H5), 3.50 (2H, t, J 6.5 Hz, isoquinolineH-3 or H-4), 3.42 (3H, s,NCH₃), 3.13 (2H, dd, J 7.0, 6.0 Hz, isoquinolineH-3 or H-4); m/z: 533[M+H]⁺ (found [M+H]⁺, 533.2296, C₃₁H₂₈N₆O₃ requires [M+H]⁺533.2296).

(S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26-7.19 (4H, m,oxobenzoxazapineH-6, H-7, 2H of C₆H₄F), 7.08 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.06-7.02 (1H, m, 1H of C₆H₄F), 7.03-6.99 (1H, m,1H of C₆H₄F), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.66(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.25 (1H, dd, J11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.19 (2H, s, CH ₂C₆H₄F), 3.40(3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹³C nmr (100 MHz, CDCl₃) δ 168.8,160.7 (d, J 245.5 Hz), 158.5, 149.2, 135.8, 131.0 (d, J 4.0 Hz), 130.9,128.9 (d, J 8.5 Hz), 126.4, 124.3 (d, J 4.0 Hz), 123.1 (d, J 15.0 Hz),122.8, 121.8, 115.3 (d, J 21.5 Hz), 99.4, 77.6, 77.0, 49.2, 35.5, 30.9,27.9, 26.3; m/z: 476 [M+H]⁺ (found [M+H]⁺, 476.2100, C₂₅H₂₆FN₅O₃requires [M+H]⁺476.2092).

(S)-1-(2,6-dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.59 (1H, s,triazoleH-5), 7.26-7.22 (3H, m, oxobenzoxazapineH-6, H-8,C₆H₃(CH₃)₂H-4), 7.12 (2H, d, J 7.5 Hz, C₆H₃(CH₃)₂H-3, H-5), 7.09 (1H, d,J 9.0 Hz, oxobenzoxazapineH-9), 5.42 (2H, s, NCH ₂C₆H₃(CH₃)₂), 5.06 (1H,dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.76 (1H, dd, J 9.5, 7.5 Hz,1H of oxobenzoxazapineH-2), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 2.31 (6H, s, C₆H₃(CH₃)₂, 1.32(9H, s, C(CH₃)₃); m/z: 486 [M+H]⁺ (found [M+H]⁺, 486.2506, C₂₈H₃₁N₅O₃requires [M+H]⁺486.2500).

(S)-5-benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m,C₆H₅, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 4.99 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.21-4.11 (1H, m, 1H of NCH ₂CH₃), 4.16 (2H, s,NCH ₂C₆H₅), 3.66 (1H, heptet, J 7.0 Hz, 1H of NCH ₂CH₃), 1.63 (6H, s,C(CH ₃)₂OH), 1.19 (3H, t, J 7.0 Hz, NCH₂CH ₃); m/z: 456 [M+H—H₂O]⁺(found [M+H]⁺, 474.2143, C₂₆H₂₇N₅O₄ requires [M+H]⁺474.2136).

(S)—N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.30-7.28 (2H, m,oxobenzoxazapineH-6, H-8), 7.26-7.21 (1H, m, 1H of C₆H₄F), 7.12 (1H, d,J 8.5 Hz, oxobenzoxazapineH-9), 7.03 (1H, br d, J 7.5 Hz, 1H of C₆H₄F),6.98 (1H, br d, J 9.5 Hz, 1H of C₆H₄F), 6.92 (1H, td, J 8.5, 2.5 Hz, 1Hof C₆H₄F), 4.97 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.65 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0,10.5 Hz, 1H of oxobenzoxazapineH-2), 4.22-4.10 (1H, m, 1H of NCH ₂CH₃),4.14 (2H, s, CH ₂C₆H₄F), 3.66 (1H, heptet, J 7.0 Hz, 1H of NCH ₂CH₃),1.63 (6H, s, C(CH ₃)₂OH), 1.19 (3H, t, J 7.0 Hz, NCH₂CH ₃); ¹⁹F nmr (380MHz, CDCl₃) δ−112.6; m/z: 474 [M+H—H₂O]⁺ (found [M+H]⁺, 492.2047C₂₆H₂₆FN₅O₄ requires [M+H]⁺492.20421).

(S)-5-benzyl-N-(7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.01 (1H, d, J 7.0 Hz, 1×NH), 7.54 (1H, s,1×NH), 7.35-7.24 (6H, m, C5H5, oxobenzoxazapineH-8), 7.10 (1H, d, J 8.5Hz, oxobenzoxazapineH-9), 7.09 (1H, m, oxobenzoxazapineH-6), 5.40 (1H,br s, 1H of C═CH₂), 5.32 (1H, br s, 1H of C═CH₂), 5.08 (1H, m,oxobenzoxazapineH-3), 4.76 (1H, dd, J 10.0, 6.0 Hz, 1H ofoxobenzoxazapineH-2), 4.33 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.18 (2H, s, CH ₂C₆H₅), 1.98 (3H, s, CCH₃); m/z:428 [M+H]⁺ (found [M+H]⁺, 428.1709, C₂₄H₂₁N₅O₃ requires [M+H]⁺428.1717).

(S)-5-benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CD₃OD) δ 7.32-7.21 (7H, m, C₆H₅, oxobenzoxazapineH-6,H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.00 (1H, dd, J 10.5,6.5 Hz, oxobenzoxazapineH-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H ofoxobenzoxazapineH-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazapineH-2),4.15 (2H, s, CH₂C₆H₅); m/z: 444, 442 [M+H]⁺ (found [M+H]⁺, 444.0492,C₁₉H₁₆BrN₅O₃ requires [M+H]⁺444.0489).

(S,Z)-5-benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41-7.39 (2H, m,oxobenzoxazapineH-6, H-8), 7.29-7.22 (5H, m, C₆H₅), 7.15 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 6.31 (1H, s, CH═CCl), 5.05 (1H, dt, J 11.5,7.5 Hz, oxobenzoxazapineH-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃), 1.57(6H, s, C(CH₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.9, 158.4,154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2,125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29.4; m/z: 480, 478[M+H—H₂O]⁺; m/z: 496, 494 [M−H]⁻ (found [M+H]⁺, 496.1743, C₂₅H₂₆ClN₅O₄requires [M+H]⁺496.1746).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28-7.20 (7H, m,oxobenzoxazapineH-6, H-8, C₆H₅), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.62 (2H, s, CCH₂N), 3.38(3H, s, NCH₃), 2.73-2.70 (4H, m, 4H of pyrrolidine), 1.86-1.82 (4H, m,4H of pyrrolidine); m/z: 485 [M+H]⁺ (found [M+H]⁺, 485.2322, C₂₇H₂₈N₆O₃requires [M+H]⁺ 485.2296).

(S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29-7.7.27 (2H,m, oxobenzoxazapineH-6, H-8), 7.25-7.18 (5H, m, C₆H₅), 7.10 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.0 Hz,oxobenzoxazapineH-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.78, 3.76 (4H, 2d ABsystem, J 4.5 Hz, 4H of morpholine), 3.50 (2H, s, CCH₂N), 3.39 (3H, s,NCH₃), 2.65, 2.63 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine); m/z:501 [M+H]⁺ (found [M+H]⁺, 501.2245, C₂₇H₂₈N₆O₄ requires [M+H]⁺501.2245).

The following examples provide a synthetic protocol for makingembodiments of pyridine-containing compounds as disclosed by the presentapplication.

Example 11

Scheme 9 provides a method for making 4-phenoxypicolinonitrile and4-phenoxypyridine-2-carboxylic acid.

With reference to Scheme 9, cesium carbonate (20.58 g, 63.1 mmol, 1.1eq) was added to a solution of 4-fluoropicolinonitrile 90 (7.00 g, 57.4mmol, 1.0 eq) and phenol 92 (5.66 g, 60.2 mmol, 1.05 eq) indimethylformamide (90 mL). The reaction was heated to 80° C. for 8 hoursand cooled. The reaction was poured into ice-water (1 L). A precipitateforms, which was isolated by filtration to obtain4-phenoxypicolinonitrile 94 (10.7 g, 95%) as a white solid; ¹H nmr (400MHz, CDCl₃) δ 8.52 (1H, d, J 6.0 Hz, pyH-6), 7.50-7.45 (2H, m, 2H ofC₆H₅), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H of C₆H₅), 7.20 (1H, d, J 2.0 Hz,pyH-3), 7.11-7.08 (2H, m, 2H of C₆H₅), 7.02 (1H, dd, J 5.5, 2.5 Hz,pyH-5); m/z: 197 [M+H]⁺.

Example 12

This example concerns a method for making 4-phenoxypyridine-2-carboxylicacid 96 from 4-phenoxypicolinonitrile 94. A suspension ofpicolinonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6M, 100 mL)was heated to 100° C. for 8 hours. The reaction was cooled to roomtemperature forming a precipitate, which was isolated by filtration. Thefiltrate was cooled generating further solid, which was isolated byfiltration and added to the first crop. The solid was dried under vacuumto obtain a white solid 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g,92%); ¹H nmr (400 MHz, D₆-DMSO) δ 8.64 (1H, d, J 6.0 Hz, pyH-6),7.57-7.53 (3H, m, pyH-3, 2H of C₆H₅), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H ofC₆H₅), 7.33 (1H, dd, J 6.0 2.5 Hz, pyH-5), 7.28-7.26 (2H, m, 2H ofC₆H₅); m/z: 216 [M+H]⁺.

Example 13

This example concerns methods for making of5-(4-fluorophenoxy)pyridine-2-carboxylic acid. N-methylpyrrolidinone (5mL) was added to a mixture of methyl fluoropicolate (0.400 g, 2.58 mmol,1.0 eq), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 eq) and cesiumcarbonate (0.925 g, 2.84 mmol, 1.1 eq). The reaction was stirred at 95°C. for 75 minutes. The reaction was cooled and added to ice-water (150mL) forming a precipitate. After stirred for 15 minutes the precipitatewas isolated by filtration. (0.540 g, 85%) as a white solid; 1H nmr (400MHz, CDCl₃) δ 8.46 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.09 (1H, dd, J 9.00.5 Hz, pyH-2), 7.24 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 7.14-7.04 (4H, m,C₆H₄F), 3.99 (3H, s, OCH₃); 19F nmr (380 MHz, CDCl₃) δ−117.0; m/z: 248[M+H]+.

Aqueous lithium hydroxide solution (0.14 g in 5 mL of water, 3.28 mmol,1.5 eq) was added to a solution of the methyl ester (0.54 g, 2.19 mmol,1.0 eq) in tetrahydrofuran (12 mL). The reaction was stirred at roomtemperature for 35 minutes and concentrated to remove the organics. Thesolution was diluted with water (5 mL) and hydrochloric acid (3M, 1 mL)added to pH-3. A white precipitate resulted, which was isolated byfiltration. Further hydrochloric acid (3M, 10 drops) was added to thefiltrate forming further precipitate, which was isolated by filtration.The precipitates were combined and dried under vacuum to obtain thetitle compound (0.49 g, 75%) as a white solid; 1H nmr (400 MHz, D6-DMSO)δ 8.43 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.02 (1H, dd, J 8.5 0.5 Hz,pyH-2), 7.39 (1H, dd, J 8.5, 3.0 Hz, pyH-4), 7.33-7.22 (4H, m, C₆H₄F);19F nmr (380 MHz, D6-DMSO) δ−117.7; m/z: 234 [M+H]+.

Example 14

This example concerns a method for making4-cyclobutyloxypyridine-2-carboxylic acid as illustrated below by Scheme10.

A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 eq) intetrahydrofuran (20 mL) was cooled to 0° C. Sodium hydride (0.154 g of a60% suspension, 3.84 mmol, 1.2 eq) was added and the reaction stirred at0° C. for 25 minutes. Fluoropicolinonitrile 100 (0.390 g, 3.20 mmol, 1.0eq) was added and the reaction was stirred at room temperature for 2hours. The reaction was quenched by the addition of NH₄Cl (5 mL). Thereaction was diluted EtOAc (80 mL) and washed with NaHCO₃(80 mL). Theaqueous phase was extracted with EtOAc (30 mL). The combined organicswere washed with brine (60 mL), dried (Na₂SO₄) and concentrated underreduced pressure. MPLC (10→60% EtOAc-hexane) yielded4-cyclobutyloxypicolinonitrile 104 (0.487 g, 88%) as a colourless oil.¹H nmr (400 MHz, CDCl₃) δ 8.46 (1H, d, J 5.5 Hz, pyH-6), 7.10 (1H, d, J2.5 Hz, pyH-3), 6.88 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.72 (1H, pentet, J7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, 2H of cBuH-2, H-4), 2.26-2.16 (2H, m,2H of cBuH-2, H-4), 1.98-1.89 (1H, m, 1H of cBuH-3), 1.82-1.71 (1H, m,1H of cBuH-3).

Hydrochloric acid (6M, 7 mL) was added to 4-cyclobutyloxypicolinonitrile104 (0.487 g, 2.80 mmol) and the reaction heated to 100° C. for 18hours. The reaction was cooled but failed to generate a precipitate. Thesolution was concentrated to dryness to obtain a beige solid4-cyclobutyloxypyridine-2-carboxylic acid 106, which was used withoutfurther purification. ¹H nmr (400 MHz, D₆-DMSO) δ 8.66 (1H, d, J 6.5 Hz,pyH-6), 7.69 (1H, dd, J 2.5 Hz, pyH-3), 7.50 (1H, dd, J 6.5, 2.5 Hz,pyH-5), 5.12 (1H, pentet, J 7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, 2H ofcBuH-2, H-4), 2.19-2.09 (2H, m, 2H of cBuH-2, H-4), 1.88-1.80 (1H, m, 1Hof cBuH-3), 1.75-1.65 (1H, m, 1H of cBuH-3); m/z: 194 [M+H]⁺.

Example 15

This example concerns a method for making(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideaccording to Scheme 11.

Dimethylformamide (80 mL) was added to a mixture ofbromooxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 eq) and copper iodide(0.31 g, 1.6 mmol, 0.1 eq). The mixture was degassed by bubbling argonthrough for five minutes. Triethylamine (11.4 mL, 81.6 mmol, 5.0 eq) wasadded followed by the hydroxyethynyloxetane 1102 (3.20 g, 32.7 mmol, 2.0eq) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05eq). The resulting brown solution was heated to 80° C. for 4 hours. Thereaction was cooled and partitioned between EtOAc (200 mL) and water(200 mL). The organics were washed with brine (150 mL), water (200 mL)and brine (150 mL), dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (10□70% EtOAc-hexane) yielded compound 1104 (6.18 g, 72%)as a yellow solid. 1H nmr (400 MHz, CD3Cl) δ 7.41-7.39 (6H, m, 6H ofC(C6H5)3), 7.25-7.15 (10H, m, 9H of C(C6H5)3, oxobenzoxazapineH-8),7.00-6.98 (2H, m, oxobenzoxazapineH-6, H-9), 4.94 (2H, d, J 7.0 Hz, 2Hof oxetaneH-2, H-4), 4.80 (2H, d, J 7.5 Hz, 2H of oxetaneH-2, H-4), 4.50(1H, dd, J 10.0, 7.0 Hz, 1H of oxobenzoxazapineH-2), 4.39 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.59-3.52 (1H, m,oxobenzoxazapineH-3), 3.29 (1H, d, J 9.0 Hz, NH), 2.89 (3H, s, NCH3).

Formic acid (50 mL) was added to the trityl protected amine 1104 (7.49g, 14.1 mmol, 1 eq) and the mixture stirred at room temperature for 4hours. Water (50 mL) was added and the reaction stirred at roomtemperature for 15 hours. The reaction was concentrated to remove someof the formic acid before diluting with water (100 mL). The organicswere extracted with EtOAc (50 mL) and set aside. The aqueous phase wasneutralized by the addition of NaOH (5M, portionwise to approximately 40mL). The organics were extracted with EtOAc (4×150 mL). The combinedneutralized organics were dried (Na₂SO₄) and concentrated under reducedpressure to obtain(S)-3-amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one1106 (3.78 g, 93%) as a yellow solid which was used without furtherpurification. 1H nmr (400 MHz, D6-DMSO) δ 7.51 (1H, d, J 2.0 Hz,oxobenzoxazapineH-6), 7.29 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8),7.14 (1H, d, J 8.0 Hz, oxobenoxazapineH-9), 4.74 (2H, d, J 7.0 Hz, 2H ofoxetaneH-2, H-4), 4.58 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.25(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.01 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.59 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.28 (3H, s, NCH3); 13C nmr (100 MHz, D6-DMSO) δ173.7, 150.7, 137.7, 130.2, 126.2, 126.6, 123.3, 119.1, 90.9, 84.5,83.7, 80.3, 66.3, 51.1, 35.1; m/z: 289 [M+H]+.

A solution of the aminooxobenzoxazapine 1106 (3.78 g, 13.13 mmol, 1.0eq) in dimethylformamide (70 mL) was degassed by bubbling nitrogenthrough for five minutes. 4-Phenoxypyridine-2-carboxylic acidhydrochloride 1108 (3.30 g, 13.13 mmol, 1.0 eq) was added and thesolution cooled to 0° C. before adding diisopropylethylamine (5.7 mL,32.81 mmol, 2.5 eq). HATU (5.49 g, 14.44 mmol, 1.1 eq) was addedportionwise and the reaction stirred at 0° C. for 1 hour and roomtemperature for 15 hours. The reaction was poured into ice-water (500mL) forming a precipitate, which after stirring for 15 minutes wasisolated by filtration. The filtrate was extracted with EtOAc (150 mL).The organic extracts were washed with brine (100 mL), water (150 mL) andbrine (100 mL), combined with the isolated precipitate, dried (Na₂SO₄)and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane)yielded(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-110 (5.20 g, 82%) as a white foam. IR (film) v 3357, 2941, 2875, 1662,1582, 1501, 1488, 1469, 1388, 1360, 1291, 1214, 1192, 1020, 979, 838,730 cm-1; 1H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44(1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H,m, 2H of C6H5), 7.32-7.29 (2H, m, 2H of C6H5 or oxobenzoxazapineH-6,H-8), 7.27-7.23 (1H, m, 1H of C6H5 or oxobenzoxazapineH-6, H-8), 7.15(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C6H5 oroxobenzoxazapineH-6, H-8), 6.50 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.93 (2H, dd, J 4.0, 0.5Hz, oxetaneH-2, H-4), 4.79 (2H, dt, J 6.5, 1.0 Hz, oxetane H-2, H-4),4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.32 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.42 (3H, s, NCH3); 13C nmr(100 MHz, CDCl3) δ 168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1,136.4, 130.9, 130.3, 126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7,88.6, 84.8, 84.5, 77.2, 67.4, 49.3, 35.4; m/z: 486 [M+H]+(found [M+H]+,486.1651, C27H23N3O6 requires [M+H]+ 486.1660).

Example 16

This example describes a method for making embodiments ofazetidinyl-acetylene compounds according to synthetic Scheme 12 below.

A. Synthesis of tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate

A solution of (trimethylsilyl)acetylene 1302 (0.71 g, 1.00 mL, 6.28mmol, 1.1 eq) in tetrahydrofuran (30 mL) was cooled to −78° C. andbutyllithium (2.51 mL of a 2.5M solution in hexane, 6.28 mmol, 1.1 eq)was added dropwise. The reaction was stirred at −78° C. for 1 hourbefore adding Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 eq). Thereaction was stirred between −78° C. and room temperature for 20 hoursbefore quenching by the addition of NH₄Cl (20 mL). The reaction waspartitioned between EtOAc (100 mL) and NH4Cl-water (1:1, 100 mL). Theorganics were washed with brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure.

The residue comprising 1304 was dissolved in tetrahydrofuran (30 mL) andcooled to 0° C. before adding tetrabutylammonium fluoride trihydrate(1.80 g, 5.71 mmol, 1.0 eq). The reaction was stirred at 0° C. for 3hours before adding NH₄Cl (20 mL). The reaction was partitioned betweenEtOAc (100 mL) and NH₄Cl-water (1:1, 100 mL). The organics were washedwith NH₄Cl (100 mL) and brine (100 mL), dried (Na₂SO₄) and concentratedunder reduced pressure to yield 1306 as a pale yellow oil. ¹H nmr (400MHz, CDCl₃) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidineH-2, H-4),4.02 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidineH-2, H-4), 2.68 (1H, s,CCH), 1.44 (9H, s, C(CH₃)₃).

B. Formation of(S)-3-hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)azetidine-1-carboxylate

Dimethylformamide (3.0 mL) was added to a mixture of thebromooxobenzoxazapine 1312 (0.141 g, 0.301 mmol, 1.0 eq) and tert-butyl3-ethynyl-3-hydroxyazetidine-1-carboxylate 1306 (0.089 g, 4.52 mmol, 1.5eq) and copper iodide (0.006 g, 0.030 mmol, 0.1 eq). The reaction wasdegassed by bubbling argon through for five minutes. Triethylamine (0.21mL, 1.506 mmol, 5.0 eq) was added forming a clear solution to which wasadded tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol, 0.05eq). A brown solution resulted, which was heated to 80° C. for 6 hours.The reaction was cooled and partitioned between EtOAc (50 mL) and water(50 mL). The organics were washed with brine (50 mL), water (50 mL) andbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure.MPLC (30→80% EtOAc-hexane) yielded starting material (0.050 g) andcompound 1314 (0.090 g, 51%); ¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz,pyH-3), 7.44-7.39 (2H, m, 2H of C₆H₅), 7.31-728 (2H, m,oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1H of C₆H₅), 7.15 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅), 6.94 (1H,dd, J 5.5, 2.5 Hz, pyH-5), 5.05 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29-4.26 (2H, m, 2H of azetidineH-2, H-4),4.12-4.09 (2H, m, 2H of azetidineH-2, H-4), 3.42 (3H, s, NCH₃), 1.45(9H, s, C(CH₃)₃); m/z: 585 [M+H]⁺, 529 [M+H—C₄H₈]⁺, 485 [M+H—C₄H₈—CO₂]⁺.

C.S)—N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

Hydrogen chloride (0.12 mL of a 4M solution in dioxane, 0.462 mmol, 3.0eq) was added to a solution of the Boc-protected azetidine 1316 (0.090g, 0.154 mmol, 1.0 eq) in ethyl acetate (1.5 mL) at room temperature.The reaction was stirred at room temperature for 6 hours Furtherhydrogen chloride (0.12 mL of a 4M solution in dioxane, 0.462 mmol, 3.0eq) was added and the reaction was stirred for a further 16 hours beforeconcentrating under reduced pressure. The residue was partitionedbetween EtOAc (30 mL) and NaHCO₃ (30 mL). The aqueous phase wasextracted with EtOAc (30 mL) and CH₂Cl₂ (3×30 mL). The combined organicswere dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (0→15%MeOH [NH₃]—CH₂Cl₂) yielded compound 1318 (0.026 g, 39%) as a whitesolid; ¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.43 (1H,d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2Hof C₆H₅), 7.31-7.29 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.22 (1H, m,1H of C₆H₅), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 7.08-7.05 (2H,m, 2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.05 (2H, d, J 9.0 Hz, 2H of azetidine-2, H-4),3.83 (2H, d, J 9.5 Hz, 2H of ozetidineH-2, H-4), 3.42 (3H, s, NCH₃);m/z: 485 [M+H]⁺ (found [M+H]⁺, 485.1826, C₂₇H₂₄N₄O₅ requires[M+H]⁺485.1819).

D. S)—N-(74(3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3, 4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

Aqueous formaldehyde solution (0.005 mL of a 37% aqueous solution, 0.071mmol, 1.5 eq) was added to the azetidine 1320 (0.023 g, 0.048 mmol, 1.0eq) in methanol (0.5 mL). The reaction was equilibrated at roomtemperature for 15 minutes before adding sodium triacetoxyborohydride(0.015 g, 0.071 mmol, 1.5 eq). After stirring at room temperature for 45minutes the reaction was quenched by the addition of Rochelle's salt (1mL). The mixture was stirred for 1 hour and partitioned between NaHCO₃(40 mL) and CH₂Cl₂ (40 mL). The aqueous phase was extracted with CH₂Cl₂(2×40 mL). The combined organics were dried (Na₂SO₄) and concentratedunder reduced pressure. MPLC (0→15% MeOH [2M NH₃]—CH₂Cl₂) yieldedcompound 1322 as a white solid. ¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz,pyH-3), 7.43-7.39 (2H, m, 2H of C₆H₅), 7.32-7.29 (2H, m,oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1H of C₆H₅), 7.13 (1H, d, J8.5 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅), 6.94 (1H,dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J Hz, 11.5, 10.0 H ofoxobenzoxazapineH-2), 3.70 (2H, br d, J 9.5 Hz, 2H of azetidineH-2,H-4), 3.44 (2H, d, J 9.0 Hz, 2H of azetidineH-2, H-4), 3.41 (3H, s,CONCHS), 2.43 (3H, s, NCH₃); m/z: 499 [M+H]⁺ (found [M+H]⁺, 499.1988,C₂₈H₂₆N₄O₅ requires [M+H]⁺499.1976).

E. Fluorination of tert-butyl(S)-3-fluoro-34(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2, 3, 4,5-tetrahydrobenzo[6][1, 4]oxazepin-7-yl)ethynyl)azetidine-1-carboxylate

To a solution of tert-butyl(S)-3-hydroxy-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)azetidine-1-carboxylate1324 (0.055 g, 0.094 mmol, 1.0 eq) in dichloromethane (1.0 mL) at −78°C. was added [bis(2-methoxyethylamino)]sulfur trifluoride (0.031 g,0.026 mL, 0.141 mmol, 1.5 eq) dropwise. The reaction was stirred at −78°C. for 3 hours and at 0° C. for 45 minutes before quenching withNaHCO₃(5 mL). The reaction was added to NaHCO₃(20 mL) and the organicsextracted with CH₂Cl₂ (3×20 mL). The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure to obtain compound 1326as a yellow oil. The crude material was used without purification; ¹Hnmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H ofC₆H₅), 7.35-7.32 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.24 (1H, m, 1Hof C₆H₅), 7.17 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.35-4.30 (5H, m, 1H of oxobenzoxazapineH-2,azetidineH-2, H-4), 3.44 (3H, s, NCH₃), 1.47 (9H, s, C(CH₃)₃); ¹⁹F nmr(380 MHz, CDCl₃) δ−141.4 (t, J 19.0 Hz); m/z: 587 [M+H]⁺, 531[M+H—C₄H₈]+, 487 [M+H—C₄H₈—CO₂]⁺.

Example 17

This example provides a method for makingN-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides throughintermediate pyrazole-1-carbonyl chloride formation according to Scheme14.

To a stirring heterogeneous mixture of 4-[(aryl)methyl]-1H-pyrazolehydrochloride 1400 (1 eq) and triphosgene (1.5 eq) in CH₂Cl₂ (15mL/mmol) under nitrogen at 0° C. was added i-Pr₂NEt (5-9 eq) over time(15 min/mmol). Red reaction solution was stirred at 0° C. for 1 h,warmed to room temperature (2 h), analyzed 4-[(aryl)methyl]-1H-pyrazoleconsumption by LC/MS and concentrated to dryness to provide 1402. Thered semi-solid concentrate was added to 1404 or the corresponding amineor its salt (1 eq) and DMAP (0.1 eq) and cooled in ice-bath undernitrogen. CH₂Cl₂ (15 mL/mmol) was added to the flask, stirred for 15 minand the stirring red solution was treated with i-Pr₂NEt (5-9 eq) overtime (15 min/mmol). Ice-bath was removed after 1 hour and allowed thereaction solution to warm to room temperature. Upon analysis of thereaction progress, the reaction solution was concentrated to dryness,diluted with water and an extractive work-up performed with either EtOAcor CH₂Cl₂. Silica gel flash column chromatographic purification of thecrude concentrate provided the requisiteN-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamide 1406 (Yield:20-75%).

Example 18

This example provides a method for makingN-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides thoughintermediate isocyanate formation according to Scheme 15.

i-Pr₂NEt (10-15 eq) over time (20 min/mmol) was added to a stirringheterogeneous mixture of compound 1420, or its corresponding amine orits salt (1 eq), and triphosgene (2.3 eq) in CH₂Cl₂ (15 mL/mmol) undernitrogen at 0° C. Pale yellow reaction solution was stirred at 0° C. for1 hour, warmed to room temperature (2 hours), analyzed correspondingamine consumption by LC/MS and concentrated to dryness. To the redsemi-solid concentrate comprising compound 1422 was added4-[(aryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 eq) and DMAP (0.1eq) and cooled in ice-bath under nitrogen. CH₂Cl₂ (15 mL/mmol) was addedto the flask, stirred for 15 minutes and the stirring red solution wastreated with i-Pr₂NEt (10-15 eq) over time (15 min/mmol). Ice-bath wasremoved after 1 hour and the reaction solution allowed to warm to roomtemperature (6-8 hours). Upon analysis of the progress, reactionsolution was concentrated to dryness, diluted with water and anextractive work-up was performed using either EtOAc or CH₂Cl₂. Silicagel flash column chromatographic purification of the resulting crudeprovided the requisiteN-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamide 1426 (Yield:19-73%).

Example 19

This example provides a method for making embodiments of disclosedalkynyl substituted compounds according to Scheme 16.

Nitrogen was bubbled through stirring solution of arylhalide 1440 (1 eq)and CuI (0.1-0.2 eq), Pd(PPh₃)₄ (0.05-0.1 eq) in dry DMF (3-4 mL/mmol)for 3 minutes in a vial. Subsequently, NEt₃ (10 eq) was added to thedark reaction solution followed by corresponding alkyne 1442 (1.5-3 eq)in quick succession. Nitrogen was bubbled through the reaction mixturefor 2 minutes, the vial capped, and the reaction mixture stirred at70-75° C. for 5-6 hours. The dark reaction solution was concentrated todryness after analyzing the reaction progression by LC/MS analysis.Crude residue was diluted with ice-water, sonicated and the slurry waswarmed to room temperature. The resulting grey/dark solid was collectedby filtration, suction dried, dissolved in THF (20 mL), filtered throughCelite®/silica gel pad, and the pad was washed with THF. Afterconcentration of the filtrate, the crude material was purified by flashchromatography to obtain alkynyl substituted analogs 1444 (Yield:25-69%).

Example 20

This example provides a method for making embodiments of disclosed4-[(aryl)methyl]-1H-pyrazole compounds according to Scheme 17.

A stirring mixture of 1-boc-pyrazole-4-boronic acid pinacol ester 1450(1 mmol), (chloromethyl)arene/hetetoarene (1.3 mmol) 1452, XPhos-Pd-G2(0.05 mmol) and K₂CO₃ (3-4 mmol) in 1,4-dioxane:H₂O (9:1, 10 mL/mmole)was degassed by high vacuum and back purged with argon in a balloon inthree cycles over a period of 5-10 minutes and heated at 70-75° C. for2-6 hours. The reaction mixture was cooled and concentrated to dryness.The crude residue was diluted with EtOAc (or CH₂Cl₂), water andsaturated aq. Na₂CO₃ (6 mL/mmol). Organic layer was separated, and theaqueous layer was extracted with EtOAc (or CH₂Cl₂). Combined organiclayers were washed with aq. NaCl, stirred over anhydrous Na₂SO₄, andfiltered through Celite®. Upon concentration of the filtrate, crude waspurified by silica gel chromatography to obtain tert-butyl4-[(aryl)methyl]-1H-pyrazole-1-carboxylate (yield 49-85%) 1454. 4.0 NHCl in 1,4-dioxane (5-7 eq) was added to stirring solution of4-[(aryl)methyl]-1H-pyrazole (1 eq) in CH₂Cl₂ (3-6 mL/mmol) at roomtemperature. Reaction mixture was stirred till the consumption oftert-butyl 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate and concentratedto dryness. The crude solid was sonicated in EtOAc (6-7 mL/mmol),filtered, washed with EtOAc on the funnel and suction dried for shorttime. Thus, collected semi-dried solid was further dried under highvacuum and obtained as a 4-[(aryl)methyl]-1H-pyrazole hydrochloride salt1456 (80-98%) and used in the next step with no further purification(purity >95%).

Example 21

This example provides a general method for making(S)—N-(5-Methyl-7-(3-methyl-3-morpholinobut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-206), as illustrated in Scheme 18.

(S)—N-(5-Methyl-7-(3-methyl-3-morpholinobut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-206): To a solution of(S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide1800 (46.8 mg, 0.1 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine 1802 (30.6mg, 0.2 mmol), CuI (1.9 mg, 0.01 mmol) and Pd(PPh₃)₄(11.6 mg, 0.01 mmol)in anhydrous DMF (1 mL) was added triethylamine (40.5 mg, 56 μL, 0.4mmol). The reaction solution was purged with nitrogen for 1 minute,sealed and heated at 70° C. for 16 hours. The reaction solution wascooled to ambient temperature and diluted with ethyl acetate (100 mL).The solution was washed with brine (20 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under the reduced pressure.Residue obtained was purified with silica gel chromatography using agradient of 0 to 100% ethyl acetate in hexane. Desired fractions werecombined and concentrated under the reduced pressure. Product obtainedwas not pure enough and further purified by reverse HPLC using agradient of 15 to 65% acetonitrile in water buffered with 0.1% formicacid. Desired fractions were combined, diluted with ethyl acetate,washed with saturated sodium bicarbonate, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under the reduced pressure.Solid obtained was dissolved in the mixture of acetonitrile and water(1/1) and lyophilized to afford(S)—N-(5-methyl-7-(3-methyl-3-morpholinobut-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-206 (27.9 mg, 52%) as a white foam solid; m/z: 541.1 [M+H]⁺.

Example 22

This example provides a general method for making(S)—N-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-207), as illustrated in Scheme 19.

4-Ethynyl-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide 1904

To a solution of tetrahydro-4H-thiopyran-4-one 1,1-dioxide 1900 (741 mg,5 mmol) in anhydrous THF (13 mL) at −78° C. was added ethynylmagnesiumbromide solution 1902 in THF (12 mL, 0.5M, 6 mmol). The resultingsolution was stirred at this temperature for 90 minutes, then warmed upto ambient temperature. The solution was cooled to −78° C. again, andsaturated ammonium chloride aqueous solution (40 mL) was added. Thesolution was extracted with ethyl acetate (2×100 mL). Combined organiclayer was washed with saturated ammonium chloride aqueous solution (30mL×2), brine (30 mL), dried over anhydrous magnesium sulfate, filteredand concentrated under the reduced pressure. Solid obtained was addeddichloromethane, partial solid precipitated and filtered. Solid waskept, and filtrate was further concentrated under the reduced pressure.Additional solid precipitated, filtered and washed with a littledichloromethane. Combined solid was dried to afford4-ethynyl-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide 1904 (492 mg,56%) as a white solid.

(S)—N-(7-((4-Hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-207) To a solution of(S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide1906 (46.8 mg, 0.1 mmol), 4-ethynyl-4-hydroxytetrahydro-2H-thiopyran1,1-dioxide 1904 (34.8 mg, 0.2 mmol), CuI (1.9 mg, 0.01 mmol) andPd(PPh₃)₄(11.6 mg, 0.01 mmol) in anhydrous DMF (1 mL) was addedtriethylamine (40.5 mg, 56 μL, 0.4 mmol). The reaction solution waspurged with nitrogen for 1 minute, then sealed and heated at 70° C. for16 hours. The reaction solution was cooled to ambient temperature anddiluted with ethyl acetate (100 mL). The solution was washed with brine(20 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated under the reduced pressure. Residue obtained was purifiedwith silica gel chromatography using a gradient of 0 to 50% acetone inhexane. Desired fractions were combined and concentrated under thereduced pressure to afford(S)—N-(7-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-207) (51 mg, 91%) as a whitesolid; m/z: 562.1 [M+H]⁺.

Example 23

This example provides a general method for making(S)—N-(7-((3-hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-209), as illustrated in Scheme 20.

3-((Trimethylsilyl)ethynyl)thietan-3-ol (2004): To a solution ofethynyltrimethylsilane 2002 (1.46 g, 2.1 mL, 14.8 mmol) in anhydrous THF(33 mL) at −78° C. was added n-BuLi (6.6 mL, 2.5M in hexane, 16.5 mmol)dropwise over 20 minutes. The reaction solution was stirred at thistemperature for 5 minutes, then allowed to warm to −20° C. and cooled to−78° C. again. A solution of thietan-3-one 2000 (1.02 g, 11.3 mmol) inanhydrous THF (5 mL) was added dropwise over 10 minutes, and reactionmixture was stirred at this temperature for 90 minutes, then warmed upto ambient temperature. Brine (40 mL) was added. The solution wasextracted with ethyl acetate (2×60 mL). Organic layer was combined,dried over anhydrous magnesium sulfate, filtered and concentrated underthe reduced pressure to afford 3-((trimethylsilyl)ethynyl)thietan-3-ol2004 (2.02 g, 96%) as a brown solid which was directly used in next stepwithout purification.

3-Hydroxy-3-((trimethylsilyl)ethynyl)thietane 1,1-dioxide 11 and3-hydroxy-3-((trimethylsilyl) ethynyl)thietane 1-oxide 2008: To asolution of 3-((trimethylsilyl)ethynyl)thietan-3-ol 2004 (1.54 g, 8.27mmol) in anhydrous dichloromethane (80 mL) at 0° C. was added mCPBA(4.08 g, 77%, 18.19 mmol). Then the resulting solution was stirred atambient temperature for 2 hours. Water (50 mL) was added and organiclayer was separated. Aqueous layer was extracted with dichloromethane(2×80 mL). Combined organic layer was washed with half saturated sodiumcarbonate solution (2×50 mL), saturated sodium bicarbonate solution (50mL), brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated under the reduced pressure. Residue obtained waspurified with silica gel chromatography using a gradient of 0 to 70%ethyl acetate in hexane. Desired fractions were combined andconcentrated under the reduced pressure to afford3-hydroxy-3-((trimethylsilyl)ethynyl)thietane 1,1-dioxide 2006 (1.57 g,87%) as a white solid and 3-hydroxy-3-((trimethylsilyl) ethynyl)thietane1-oxide 2008 (130 mg, 11%) as a white solid.

3-Ethynyl-3-hydroxythietane 1-oxide 2010: To a solution of3-hydroxy-3-((trimethylsilyl) ethynyl)thietane 1-oxide 2008: (125 mg,0.57 mmol) in anhydrous THF (6 mL) at 0° C. was added TBAF (0.58 mL,1.0M in THF, 0.58 mmol). The resulting solution was stirred at thistemperature for 10 minutes. Water (20 mL) and ethyl acetate (100 mL)were added. Organic layer was separated, washed with brine (2×15 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated underthe reduced pressure. Residue obtained was purified with silica gelchromatography using a gradient of 0 to 100% ethyl acetate in hexane.Desired fractions were combined and concentrated under the reducedpressure to afford 3-ethynyl-3-hydroxythietane 1-oxide 2010 (15.9 mg,19%) as a white solid.

(S)—N-(7-((3-Hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-208): To a solution of(S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide2012 (51 mg, 0.11 mmol), 3-ethynyl-3-hydroxythietane 1-oxide 2010 (15.9mg, 0.12 mmol), CuI (2.0 mg, 0.011 mmol) and Pd(PPh₃)₄(12.6 mg, 0.011mmol) in anhydrous DMF (1 mL) was added triethylamine (44.1 mg, 61 μL,0.44 mmol). The reaction solution was purged with nitrogen for 1 minute,then sealed and heated at 70° C. for 16 hours. The reaction solution wascooled to ambient temperature and diluted with ethyl acetate (100 mL).The solution was washed with brine (20 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under the reduced pressure.Residue was purified with silica gel chromatography using a gradient of0 to 70% acetone in hexane to give desired product which was not pureenough and further purified by reverse HPLC using a gradient of 25 to75% acetonitrile in water buffered with 0.1% formic acid. Desiredfractions were combined, diluted with ethyl acetate (100 mL), washedwith saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under the reduced pressure. Solidobtained was dissolved in the mixture of acetonitrile and water (1/1)and lyophilized to afford(S)—N-(7-((3-hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide I-208 (14.5 mg, 26%) as a white foam solid; m/z: 518.1 [M+H]⁺.

(S)—N-(7-((3-hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-209: To a solution of(S)—N-(7-((3-hydroxy-1-oxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-208 (11.3 mg, 0.022 mmol) in anhydrous dichloromethane (1 mL) at 0° C.was added mCPBA (5 mg, 77%, 0.022 mmol). The resulting solution wasstirred at ambient temperature for 2.5 hours. Two drops of water wasadded to quench the reaction. All solvents were removed under thereduced pressure. Residue obtained was purified by reverse HPLC using agradient of 20 to 80% acetonitrile in water buffered with 0.1% formicacid. Desired fractions were combined, diluted with ethyl acetate (100mL), washed with saturated sodium bicarbonate, brine, dried overanhydrous magnesium sulfate, filtered and concentrated under the reducedpressure. Solid obtained was dissolved in the mixture of acetonitrileand water (1/1) and lyophilized to afford(S)—N-(7-((3-hydroxy-1,1-dioxidothietan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-209 (11 mg, 95%) as a white foam solid; m/z: 534.0 [M+1]⁺.

Example 24

This example provides a general method for making(S)—N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-210), as illustrated in Scheme 21.

(S)—N-(5-Methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-210): The solution of(S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide2100 (46.8 mg, 0.1 mmol), pyrrolidine 2104 (107 mg, 124 μL, 1.5 mmol),potassium carbonate (34.5 mg, 0.25 mmol), CuI (1.9 mg, 0.01 mmol) andPd(PPh₃)₄(11.6 mg, 0.01 mmol) in anhydrous DMF (1 mL) was purged withnitrogen for 1 minute, then 3-chloro-3-methylbut-1-yne 2102 (51.3 mg, 56μL, 0.5 mmol) was added. The reaction vial was sealed and heated at 70°C. for 16 hours. The reaction solution was cooled to ambient temperatureand diluted with ethyl acetate (100 mL). The solution was washed withbrine (20 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated under the reduced pressure. Residue was purified withsilica gel chromatography using a gradient of 0 to 5% methanol indichloromethane buffered with 0.1% NH₃ Desired fractions were combinedand concentrated under the reduced pressure. Product obtained wasdissolved in the mixture of acetonitrile and water (1/1) and lyophilizedto afford(S)—N-(5-methyl-7-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-210 (28.7 mg, 55%) as a white foam solid; m/z: 525.2 [M+H]⁺.

Example 25

This example provides a general method for making(S)—N-(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-211), as illustrated in Scheme 22.

(S)—N-(7-(3-(1,1-Dioxidothiomorpholino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-211): The solution of(S)—N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide2200 (46.8 mg, 0.1 mmol), thiomorpholine 1,1-dioxide 2204 (135 mg, 1mmol), potassium carbonate (34.5 mg, 0.25 mmol), CuI (1.9 mg, 0.01 mmol)and Pd(PPh₃)₄ (11.6 mg, 0.01 mmol) in anhydrous DMF (1 mL) was purgedwith nitrogen for 1 minute, then 3-chloro-3-methylbut-1-yne 2202 (51.3mg, 56 μL, 0.5 mmol) was added. The reaction vial was sealed and heatedat 70° C. for 16 hours. The reaction solution was cooled to ambienttemperature and diluted with ethyl acetate (100 mL). The solution waswashed with brine (20 mL), dried over anhydrous magnesium sulfate,filtered and concentrated under the reduced pressure. Residue obtainedwas purified with silica gel chromatography using a gradient of 0 to 80%ethyl acetate in hexane to afford desired product. The product was notpure enough and further purified by reverse HPLC using a gradient of 40to 70% acetonitrile in water buffered with 0.1% formic acid. Desiredfractions were combined, diluted with ethyl acetate (100 mL), washedwith saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under the reduced pressure. Solidobtained was dissolved in the mixture of acetonitrile and water (1/1)and lyophilized to afford(S)—N-(7-(3-(1,1-dioxidothiomorpholino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-211 (12.5 mg, 21%) as a white foam solid; m/z: 589.2 [M+H]⁺.

Example 26

This example concerns a method for making2-ethynylspiro[3.3]heptan-2-ol, shown below.

To a stirring solution of2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 8.2 mmol) indry Et2O (30 mL) at 0° C. under nitrogen was added solid n-Bu₄NF.3H₂Oall at once. After 2 hours, clear pale brown reaction solution wasquenched with saturated aqueous aq. NH₄Cl (10 mL) slowly over a periodof 10 minutes, warmed to room temperature, diluted with H₂O (6 mL) andEt₂O (20 mL). Upon separating the organic layer, the aqueous layer wasextracted with additional Et₂O (3×20 mL). Upon washing the combinedorganic layers with water (10 mL), aqueous NaHCO₃(10 mL) and brinesuccessively, the organic layer was separated, stirred over anhydrousNa₂SO₄, polish filtered, concentrated and ethynylspiro[3.3]heptan-2-ol(1.11 g, 99%) was obtained as a faint brown liquid. The title compoundthus obtained was used in the next step with no further purification. 1HNMR (400 MHz, Chloroform-d) δ 2.58-2.46 (m, 3H), 2.43 (br s, 1H),2.30-2.21 (m, 2H), 2.16-2.06 (m, 2H), 2.09-1.95 (m, 2H), 1.89-1.76 (m,2H). (PMA, KMnO₄ and ammonium molybdate stains were used to followreaction progress).

Example 27

This example concerns a method for making2-((trimethylsilyl)ethynyl)spiro-[3.3]heptan-2-ol, shown below.

A two neck flask containing a stir bar was heated, cooled to roomtemperature under vacuum and back filled with argon by balloon.Trimethylsilylacetylene (1.4 mL, 1.0 g, 10.2 mmol) followed by dry THFwere transferred to flask and cooled to −78° C. n-BuLi (1.6 M solutionin hexanes, 7.0 mL, 11.2 mmol) was added dropwise for a period of 15minutes to the above stirring solution. After 30 minutes, to thereaction solution was added spiro[3.3]heptanone (1.0 mL, 1.0 g, 9.09mmol) for 15 minutes, stirred for 1 hour at the same temperature and at0° C. for 1 hour. Reaction solution was quenched with ice cold aq. NH₄Cl(5 mL) slowly, concentrated to remove volatiles diluted with Et₂O (30mL) and H2O (10 mL). Upon separating the organic layer, aqueous layerwas extracted with additional Et₂O (2×20 mL). Combined organic layerswere washed with brine (15 mL), stirred over anhydrous Na₂SO₄, polishfiltered and concentrated. Upon drying the crude concentrate under highvacuum 2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol (1.71 g, 81%)was provided as a white solid which was used in the next step with nofurther purification. 1H NMR (400 MHz, Chloroform-d) δ 2.54-2.43 (m,2H), 2.26-2.19 (m, 2H), 2.12 (s, 1H), 2.12-2.07 (m, 2H), 2.04-1.93 (m,2H), 1.88-1.75 (m, 2H), 0.15 (s, 9H). (PMA, KMnO₄ and ammonium molybdatestains were used to follow reaction progress).

Example 28

This example concerns a method for making6-ethynyl-2-oxaspiro[3.3]heptan-6-ol, shown below.

6-Ethynyl-2-oxaspiro[3.3]heptan-6-ol was prepared in the similar mannerto the preparation of 2-ethynylspiro[3.3]heptan-2-ol and obtained as apale brown solid and used in the next step with further purification. 1HNMR (400 MHz, Chloroform-d) δ 4.74 (s, 2H), 4.66 (s, 2H), 2.76-2.67 (m,2H), 2.50 (s, 1H), 2.48-2.39 (m, 2H), 2.24 (s, 1H).

Example 29

This example concerns a method for making6-((Trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol, shown below.

Analogous to the preparation of2-((trimethylsilyl)ethynyl)spiro[3.3]heptan-2-ol,6-((trimethylsilyl)ethynyl)-2-oxaspiro[3.3]heptan-6-ol was obtained bythe reaction of trimethylsilyl lithium acetylide with2-oxaspiro[3.3]heptan-6-one as a crude pale brown solid and used in thenext step with no further purification. 1H NMR (400 MHz, Chloroform-d) δ4.75-4.62 (m, 4H)), 2.77-2.60 (m, 2H), 2.47-2.36 (m, 2H), 2.23 (s, 1H),0.14 (s, 9H).

Example 30

This example concerns a method for making1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine by modified procedure ofImada, Y.; Yurasa, M.; Nakamura, I.; Murahashi, S.-i. J. Org. Chem.1998, 63, 2342-2347.

To a stirring pale green solution of CuCl (0.10 g, 10 mmol) in dry THFunder argon at room temperature, 1-methylpiperazine (1.10 g, 1.22 mL, 11mmol) NEt₃ (1.11 g, 1.53 mL 11 mmol) were added successively over aperiod of 20 minutes. After stirring the blue heterogeneous mixture for10 minutes, 2-methylbut-3-yn-2-yl acetate (1.27 g, 10 mmol) (Lepronier,A.; Achard, T.; Giordano, L.; Tenaglia, A.; Buono, G.; Clavier, H. Adv.Synth. Catal. 2016. 358 (4), 631-642. Bartoli, G.; Bosco, M.; Dalpozzo,R.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.; Sambri, L. Synlett2003, 39-42.) in dry THF (5 mL) was added slowly over a period of 20minutes and a mild exotherm was observed. The reaction mixture wasstirred for 30 minutes, heated at 58° C. for 7 hours and cooled.Brownish red reaction mixture was diluted with Et₂O (70 mL) and aqueousNaHCO₃(40 mL). Upon separating organic layer, red colored heterogeneousaqueous layer was extracted with Et₂O (3×75 mL). Combined pale greenorganic layers were washed with aqueous NaHCO₃(40 mL) followed byaqueous NaCl successively, stirred over anhydrous Na₂SO₄ and filteredthrough Celite®. Filtrate was concentrated and obtained the titlecompound as a crude yellow solid (1.16 g). Further purification bysilica gel chromatography (Combiflash® Teledyne RediSep® 12G goldcolumn. A: CH₂Cl₂ B B: 20% MeOH/CH₂Cl₂ @15% B/A. Detection 220 and 230nm) provided an off-white solid (0.54 g, yield 33%). 1H NMR (400 MHz,Chloroform-d) δ 2.67 (br s, 4H), 2.46 (br s, 4H), 2.26 (app s, 4H), 1.37(s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 85.55, 71.50, 55.45, 53.82,46.64, 45.88, 27.71.

Exemplary embodiments of compounds according to the present disclosurehave been made according to disclosed synthetic schemes, andcharacterization data for such compounds is provided below.

(S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-100)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 6.0Hz, pyH-6), 7.57 (1H, d, J 2.5 Hz, pyH-5), 7.27 (2H, d, J 7.5 Hz, 2H ofC₆H₄F), 7.13-7.08 (3H, m, 2H of C₆H₄F, 1H of oxobenzoxazapineH-6, H-8,H-9), 7.06-7.02 (2H, m, 1H of oxobenzoxazapineH-6, H-8, H-9), 6.92 (1H,dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 168.9, 166.1, 163.5, 160.1 (d, J 244.5 Hz),151.4, 150.2, 150.0, 149.5 (d, J 2.5 Hz), 136.2, 130.8, 126.5, 123.0,122.4 (d, J 8.5 Hz), 120.3, 117.0 (d, J 23.5 Hz), 114.2, 110.2, 94.5,80.7, 77.2, 65.6, 49.4, 35.4, 31.4; ¹⁹F nmr (380 MHz, CDCl₃) δ−116.6;m/z: 490 [M+H]⁺ (found [M+H]⁺, 490.1793, C₂₅H₂₄FN₃O₅ requires[M+H]⁺490.1773).

(S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide(I-101)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.57 (1H, d, J 2.5 Hz, pyH-5), 7.33-7.23 (3H, m, 3H ofC₆H₄F, oxobenzoxazapineH-6, H-8, H-9), 7.13-7.04 (4H, m, 4H of C₆H₄F,oxobenzoxazapineH-6, H-8, H-9), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5),5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5,7.5 Hz, 1H of oxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹⁹F nmr(380 MHz, CDCl₃) δ−116.6; m/z: 488 [M+H]⁺ (found [M+H]⁺, 488.1985,C₂₈H₂₆FN₃O₄ requires [M+H]⁺488.1980).

(S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2-fluorophenoxy)picolinamide(I-102)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.46 (1H, d, J 6.0Hz, pyH-6), 7.57 (1H, d, J 2.5 Hz, pyH-3), 7.25-7.21 (4H, m, 4H, ofC₆H₄F, oxobenzoxazapineH-6, H-8), 7.19-7.16 (2H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.96 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹⁹F nmr(380 MHz, CDCl₃) δ−128.9; m/z: 488 [M+H]⁺ (found [M+H]⁺, 488.1997,C₂₈H₂₆FN304 requires [M+H]⁺488.1980).

(S)-4-(2-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-103)

¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J 7.0 Hz, NH), 8.46 (1H, d, J 6.0Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.28-7.16 (6H, m,oxobenzoxazapineH-6, H-8, C₆H₄F), 7.12 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 6.96 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt,J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); ¹⁹Fnmr (380 MHz, CDCl₃) δ−128.9; m/z: 490 [M+H]⁺ (found [M+H]⁺, 490.1768,C₂₇H₂₄FN₃O₅ requires [M+H]⁺490.1773).

(S)-4-(2,4-difluorophenoxy)-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-104)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.47 (1H, d, J 5.5Hz, pyH-6), 7.54 (1H, d, J 2.5 Hz, pyH-3), 7.25-7.22 (2H, m,oxobenzoxazapineH-6, H-8), 7.15 (1H, td, J 9.0, 5.5 Hz, 1H of C₆H₃F₂),7.09 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.01-6.90 (3H, pyH-5, 2H ofC₆H₃F₂), 5.00 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.27 (1H, dd, J 11.0, 9.5Hz, 1H of oxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 1.32 (9H, s,C(CH₃)₃); ¹⁹F nmr (380 MHz, CDCl₃) δ−111.8, −123.7; m/z: 506 [M+H]⁺.

(S)-4-(2,4-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-105)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.46 (1H, d, J 5.5Hz, pyH-6), 7.54 (1H, d, J 2.5 Hz, pyH-3), 7.28-7.26 (2H, m,oxobenzoxazapineH-6, H-8), 7.15 (1H, td, J 9.0, 5.5 Hz, 1H of C₆H₃F₂),7.00-6.90 (3H, m, pyH-5, 2H of C₆H₃F₂), 5.01 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 168.9, 165.5, 163.4, 160.1 (dd, J 248.5, 10.5Hz), 154.4 (dd, J 253.5, 12.5 Hz), 151.5, 150.2, 150.0, 136.9 (dd, J12.5, 4.0 Hz), 136.2, 130.8, 126.4, 124.1 (dd, 10.0, 1.5 Hz), 123.0,120.3, 113.5, 112.1 (dd, J 23.0, 4.0 Hz), 109.4, 106.0 (dd, J 26.5, 22.0Hz), 94.5, 80.7, 77.1, 65.6, 49.4, 35.4, 31.4; ¹⁹F nmr (380 MHz, CDCl₃)δ−111.7, −123.7; m/z: 508 [M+H]⁺, 490 [M+H—H₂O]⁺ (found [M+H]⁺,508.1671, C₂₇H₂₃F₂N₃O₅ requires [M+H]⁺ 508.1679).

(S)—N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide(I-106)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.5Hz, pyH-6), 7.62 (1H, d, J 2.5 Hz, pyH-3), 7.37 (1H, td, J 8.0, 6.5 Hz,C₆H₄F H-5), 7.26-7.23 (2H, m, oxobenzoxazapineH-6, H-8), 7.09 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 6.96(1H, ddd, J 8.0, 2.5, 1.0 Hz, C₆H₄F H-4 or H-6), 6.86 (1H, dd, J 8.0,2.5 Hz, C₆H₄F H-4 or H-6), 6.81 (1H, dt, J 9.5, 2.5 Hz, C₆H₄F H-2), 5.01(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 1.32 (9H, s, C(CH₃)₃); ¹³C nmr(100 MHz, CDCl₃) δ 169.0, 165.4, 163.5 (d, J 249.0 Hz), 163.4, 154.8,151.6, 150.2, 149.4, 136.0, 131.1 (d, J 9.5 Hz), 130.8, 126.3, 122.8,121.7, 116.3 (d, J 3.2 Hz), 114.7, 112.7 (d, J 20.5 Hz), 110.8, 108.6(d, J 24.0 Hz), 99.3, 77.6, 77.2, 49.4, 35.4, 30.9, 27.9; ¹⁹F nmr (380MHz, CDCl₃) δ−109.5; m/z: 488 [M+H]⁺.

(S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-107)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.47 (1H, d, J 5.5Hz, pyH-6), 7.62 (1H, d, J 2.5 Hz, pyH-3), 7.36 (1H, dt, J 8.0, 6.5 Hz,C₆H₄F H-5), 7.27-7.25 (2H, m, oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5),6.96-6.93 (1H, m, C₆H₄F H-4 or H-6), 6.86 (1H, dd, J 8.0, 2.5 Hz, C₆H₄FH-4 or H-6), 6.80 (1H, dt, J 9.5, 2.5 Hz, C₆H₄F H-2), 5.02 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); ¹³Cnmr (100 MHz, CDCl₃) δ 168.9, 165.4, 163.5 (d, J 249.0 Hz), 163.5, 154.9(d, J 10.5 Hz), 151.5, 150.3, 150.0, 136.2, 131.2 (d, J 9.5 Hz), 130.8,126.5, 123.0, 120.3, 116.3 (d, J 3.5 Hz), 114.7, 112.7 (d, J 20.5 Hz),110.8, 108.6 (d, J 24.5 Hz), 94.5, 80.6, 77.2, 65.5, 49.4, 35.4, 31.4;¹⁹F nmr (380 MHz, CDCl₃) δ−109.5; m/z: 490 [M+H]⁺, 472 [M+H—H₂O]⁺ (found[M+H]⁺, 490.1766, C₂₇H₂₄FN₃O₅ requires [M+H]⁺490.1773).

(S)—N-(7-isopentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-108)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.27-7.23 (1H, m, 1H of C₆H₅), 7.09-7.03 (4H, m, 2H of C₆H₅,oxobenzoxazapineH-8 or H-9), 7.01 (1H, br s, oxobenzoxazapineH-6), 6.94(1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.05 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 2.63-2.59 (2H, m, CH₂CH₂CH(CH₃)₂), 1.61 (1H, heptet, J 6.5 Hz, CH₂CH₂CH(CH₃)₂), 1.52-1.47(2H, m, CH₂CH ₂CH(CH₃)₂), 0.95 (6H, d, J 6.5 Hz, CH₂CH₂CH(CH ₃)₂); m/z:460 [M+H]⁺.

(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-110)

IR (film) v 3357, 2941, 2875, 1662, 1582, 1501, 1488, 1469, 1388, 1360,1291, 1214, 1192, 1020, 979, 838, 730 cm⁻¹; ¹H nmr (400 MHz, CDCl₃) δ8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d,J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H of C₆H₅), 7.32-7.29 (2H, m, 2H ofC₆H₅ or oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1H of C₆H₅ oroxobenzoxazapineH-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),7.08-7.06 (2H, m, 2H of C₆H₅ or oxobenzoxazapineH-6, H-8), 6.50 (1H, dd,J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, dd, J 4.0, 0.5 Hz, oxetaneH-2, H-4),4.79 (2H, dt, J 6.5, 1.0 Hz, oxetaneH-2, H-4), 4.71 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); ¹³C nmr (100 MHz, CDCl₃) δ168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1, 136.4, 130.9, 130.3,126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7, 88.6, 84.8, 84.5, 77.2,67.4, 49.3, 35.4; m/z: 486 [M+H]⁺ (found [M+H]⁺, 486.1651, C₂₇H₂₃N₃O₆requires [M+H]⁺486.1660).

(S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-111)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.57 (1H, J 2.5 Hz, pyH-3), 7.32-7.30 (2H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-8, H-9), 7.15 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.13-7.09 (2H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-8, H-9), 7.06-7.02 (2H, m, 2H of C₆H₄F,oxobenzoxazapineH-6, H-8), 6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.92 (2H, ddd, J 6.5,3.0, 0.5 Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, dt, J 6.5, 1.0 Hz, 2H ofoxetaneH-2, H-4), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CDCl₃)δ−116.5; m/z: 504 [M+H]⁺ (found [M+H]⁺, 504.1568, C₂₇H₂₂FN₃O₆ requires[M+H]⁺ 504.1565).

(S)-4-(2-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-112)

¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J 7.0 Hz, NH), 8.46 (1H, d, J 5.5Hz, pyH-6), 7.58 (1H, d, J 2.5 Hz, pyH-3), 7.32-7.29 (2H, m, 2H ofC₆H₄F, oxobenzoxazapineH-6, H-8), 7.26-7.16 (4H, m, 4H of C₆H₄F,oxobenzoxazapineH-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.92 (2H, ddd, J 6.5, 3.0, 1.0 Hz, 2H ofoxetaneH-2, H-4), 4.79 (2H, ddd, J 6.5, 1.5, 1.0 Hz, 2H of oxetaneH-2,H-4), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.31 (1H,dd, J 11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.42 (3H, s, NCH₃); ¹⁹Fnmr (380 MHz, CDCl₃) δ−128.9; m/z: 504 [M+H]⁺ (found [M+H]⁺, 504.1564,C₂₇H₂₂FN₃O₆ requires [M+H]⁺ 504.1565).

(R)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-113)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.0 Hz, pyH-3), 7.41 (2H, t, J 8.0 Hz, 2H ofC₆H₅), 7.27-7.23 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.06 (2H, d, J 7.5 Hz, 2H ofC₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.0Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂OH); m/z:472 [M+H]⁺ (found [M+H]⁺, 472.1860, C₂₇H₂₅N₃ 05 requires [M+H]⁺472.1867).

(S)-4-(2,4-difluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-114)

¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 6.0Hz, pyH-6), 7.55 (1H, d, J 2.5 Hz, pyH-3), 7.33-7.30 (2H, m,oxobenzoxazapineH-6, H-8), 7.19-7.13 (1H, m, 1H of C₆H₃F₂), 7.16 (1H, d,J 9.0 Hz, oxobenzoxazapineH-9), 7.01-6.91 (2H, m, 2H of C₆H₃F₂), 6.95(1H, dd, J 6.0, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, m, 2H of oxtetaneH-2, H-4), 4.80 (2H, d,J 6.5 Hz, 2H of oxetaneH-2, H-4), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CDCl₃)δ−111.7, −123.7; m/z: 522 [M+H]⁺ (found [M+H]⁺, 522.1484, C₂₇H₂₁F₂N₃O₆requires [M+H]⁺522.1471).

(S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-115)

¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.48 (1H, d, J 5.5Hz, pyH-6), 7.63 (1H, d, J 2.5 Hz, pyH-3), 7.37 (1H, td, J 8.0, 6.5 Hz,C₆H₄F H-5), 7.32-7.30 (2H, m, oxobenzoxazapineH-6, H-8), 7.15 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 6.98 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 6.96(1H, ddd, J 8.5, 2.5, 1.0 Hz, 1H of C₆H₄F), 6.86 (1H, dd, J 8.0, 2.5 Hz,1H of C₆H₄F), 6.81 (1H, dt, J 9.5, 2.5 Hz, 1H of C₆H₄F), 5.04 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.93 (2H, ddd, J 6.5, 2.5, 0.5 Hz,2H of oxetaneH-2, H-4), 4.79 (2H, d, J 6.5 Hz, 2H of oxetaneH-2, H-4),4.72 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.32 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.43 (3H, s, NCH₃); ¹⁹F nmr(380 MHz, CDCl₃) δ−109.5; m/z: 504 [M+H]⁺ (found [M+H]⁺, 504.1574,C₂₇H₂₂FN₃O₆ requires [M+H]⁺ 504.1565).

(S)—N-(5-methyl-4-oxo-7-(3-(pyrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-116)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.0 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.29-7.23 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.62 (2H, s, CCH₂N), 3.42 (3H, s, NCH₃), 2.72-2.68(4H, m, 4H of pyrrolidine), 1.86-1.83 (4H, m, 4H of pyrrolidine); m/z:497 [M+H]⁺ (found [M+H]⁺, 497.2209, C₂₉H₂₈N₄O₄ requires [M+H]⁺497.2183).

(S)—N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-117)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.30-7.23 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.12(1H, d, J 9.0, Hz, oxobenzoxazapineH-9), 7.08-7.05 (2H, m, 2H of C₆H₅),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.78, 3.77 (4H, 2d AB system, J 4.5 Hz, 4H ofmorpholine), 3.50 (2H, s, NCH₂C), 3.42 (3H, s, NCH₃), 2.65, 2.63 (4H, 2dAB system, J 4.5 Hz, 4H of morpholine); m/z: 513 [M+H]⁺ (found [M+H]⁺,513.2183, C₂₉H₂₈N₄O₅ requires [M+H]⁺513.2132).

(S)-4-(2,6-difluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-118)

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.0 Hz, NH), 8.48 (1H, d, J 5.5Hz, pyH-6), 7.57 (1H, d, J 2.5 Hz, pyH-3), 7.27-7.25 (2H, m,oxobenzoxazapineH-6, H-8), 7.24-7.18 (1H, m, 1H of C₆H₃F₂), 7.11 (1H, d,J Hz, oxobenzoxazapineH-9), 7.03 (2H, dd, J 8.5, 8.0 Hz, 2H of C₆H₃F₂),7.00 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.61 (6H, s, C(CH₃)₂OH); ¹⁹Fnmr (380 MHz, CDCl₃) δ−126.0; m/z: 508 [M+H]⁺, 490 [M+H—H₂O]⁺ (found[M+H]⁺, 508.1670, C₂₇H₂₃F₂N₃O₅ requires [M+H]⁺508.1679).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-methyl-4-phenoxypicolinamide(I-119)

¹H nmr (400 MHz, CDCl₃) δ 8.89 (1H, d, J 7.5 Hz, NH), 7.44 (1H, d, J 2.0Hz, pyH-3), 7.42-7.38 (2H, m, 2H of C₆H₅), 7.28-7.25 (2H, m,oxobenzoxazapineH-6, H-8), 725-7.22 (1H, m, 1H of C₆H₅), 7.12 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 7.06-7.04 (2H, m, 2H of C₆H₅), 6.75 (1H,d, J 2.0 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3),4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 2.52 (3H,s, pyCH₃), 1.62 (6H, s, C(CH₃)₂OH); m/z: 486 [M+H]⁺ (found [M+H]⁺,486.2022, C₂₈H₂₇N₃O₅ requires [M+H]⁺ 486.2023).

(S)—N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-120)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.31-7.23 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.13(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 2.57-2.51 (2H, m, 2H of cBu),2.39-2.31 (2H, m, 2H of cBu), 1.93-1.86 (2H, m, 2H of cBu); ¹³C nmr (100MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1 (2C), 136.2,130.9, 130.3, 126.5, 125.7, 123.1, 120.7, 120.3, 114.4, 110.6, 93.2,82.0, 77.2, 68.3, 49.4, 38.5, 35.4, 13.0; m/z: 484 [M+H]⁺ (found [M+H]⁺,484.1873, C₂₈H₂₅N₃O₅ requires [M+H]⁺ 484.1867).

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenoxypicolinamide(I-121)

¹H nmr (400 MHz, CDCl₃) δ 8.71 (1H, d, J 7.0 Hz, NH), 8.34 (1H, d, J 2.5Hz, pyH-6), 8.03 (1H, d, J 8.5 Hz, pyH-3), 7.42-7.38 (2H, m, 2H ofC₆H₅), 7.30-7.26 (3H, m, pyH-4, oxobenzoxazapineH-6, H-8), 7.24-7.20(1H, m, 1H of C₆H₅), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),7.07-7.04 (2H, m, 2H of C₆H₅), 5.05 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂)OH); m/z:490 [M+H]+, 472 [M+H—H₂O]⁺ (found [M+H]⁺, 490.1854, C₂₇H₂₅N₃O₅ requires[M+H]⁺490.1867).

(S)-5-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-122)

¹H nmr (400 MHz, CDCl₃) δ 8.69 (1H, d, J 7.5 Hz, NH), 8.31 (1H, d, J 2.5Hz, pyH-6), 8.03 (1H, d, J 8.5 Hz, pyH-3), 7.28-7.24 (3H, m, 3×ArH),7.13-7.01 (5H, m, 5×ArH), 5.05 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.62 (6H, s, C(CH ₃)₂)OH); ¹⁹Fnmr (380 MHz, CDCl₃) δ−117.4 (tt, J 8.0, 4.0 Hz); m/z: 528 [M+H]⁺, 510[M+H—H₂O]⁺ (found [M+H]⁺, 490.1772, C₂₇H₂₄FN₃O₅ requires[M+H]⁺490.1773).

(S)—N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-123)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.31-7.23 (3H, m, 1H of C₆H₅, BzoxazapineH-6, H-8), 7.13 (1H, d,J 9.0 Hz, BzoxazapineH-9), 7.08-7.05 (2H, m, 2H of C₆H₅), 6.94 (1H, dd,J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.95 (2H, dt, J 12.5, 4.5 Hz, 2H of pyranH-2,H-6), 3.71 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H of pyranH-2, H-6), 3.43(3H, s, NCH₃), 2.08-2.00 (2H, m, 2H of pyranH-3, H-5), 1.89 (2H, ddd, J13.0, 9.0, 4.0 Hz, 2H of pyranH-3, H-5); m/z: 514 [M+H]⁺ (found [M+H]⁺,514.1973, C₂₉H₂₇N₃O₆ requires [M+H]⁺514.1973).

(S)—N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.0 Hz, pyH-3), 7.42-7.38 (2H, m, 2H ofC₆H₅), 7.29-7.20 (4H, m, 1H of C₆H₅, BzazapineH-6, H-8, H-9), 7.07-7.05(2H, m, 2H of C₆H₅), 6.92 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.93 (2H, d, J7.0 Hz, 2H of oxetaneH-2, H-4), 4.79 (2H, dd, J 7.0, 1.0 Hz, 2H ofoxetaneH-2, H-4), 4.60 (1H, td, J 11.0, 7.5 Hz, BzazapineH-3), 3.42 (3H,s, NCH₃), 2.95-2.86 (1H, m, 1H of BzazapineH-5), 2.75-2.63 (2H, m, 1H ofBzazapineH-5, 1H of BzazapineH-4), 2.12-2.04 (1H, m, 1H ofBzazapineH-4); m/z: 484 [M+H]⁺ (found [M+H]⁺, 484.1867, C₂₈H₂₅N₃O₅requires [M+H]⁺484.1867).

(S)-4-(2,6-dimethylphenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-124)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.38 (1H, d, J 6.0Hz, pyH-6), 7.48 (1H, d, J 2.5 Hz, pyH-3), 7.27-7.24 (3H, m,oxobenzoxazapineH-6, H-8, C₆H₃(CH₃)2H-4), 7.11 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.08 (2H, s, C₆H₃(CH₃)₂H-2, H-6), 6.74 (1H, dd, J5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3),4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J11.5, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.41 (3H, s, NCH₃), 2.05 (6H,s, 2×ArCH₃), 1.61 (6H, s, C(CH ₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 169.0,165.3, 163.8, 151.4, 150.2, 150.0, 149.6, 136.2, 130.8, 130.7, 129.3,126.4, 126.1, 123.0, 120.3, 112.5, 109.3, 94.4, 80.7, 77.2, 65.6, 49.3,35.4, 31.4, 16.1; m/z: 500 [M+H]⁺.

(S)-4-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-125)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.47 (1H, d, J 5.0Hz, pyH-6), 7.90 (1H, d, J 1.0 Hz, pyH-3), 7.28-7.24 (2H, m,oxobenzoxazapineH-6, H-8), 7.17 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.11(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.11-7.07 (2H, m, 2H of C₆H₄F),6.97 (2H, tt, J 9.0, 2.0 Hz, 2H of C₆H₄F), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.97 (2H, s, CH ₂C₆H₄F), 3.41 (3H, s, NCH₃), 1.61(6H, s, C(CH ₃)₂OH); ¹⁹F nmr (380 MHz, CDCl₃) δ−116.0 (tt, J 8.0, 5.5Hz); m/z: 488 [M+H]⁺ (found [M+H]⁺, 488.1986, C₂₅H₂₆FN₃O₄ requires[M+H]⁺ 488.1980).

(S)-4-(4-fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-126)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.47 (1H, dd, J5.0, 1.5 Hz, pyH-6), 7.90 (1H, br d, J 1.0 Hz, pyH-3), 7.31-7.29 (2H, m,oxobenzoxazapineH-6, H-8), 7.18 (1H, dd, J 5.0, 2.0 Hz, pyH-5), 7.14(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.11-7.07 (2H, m, 2H of C₆H₄F),6.96 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 5.04 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.91 (2H, dd, J 6.5, 4.5 Hz, 2H of oxetaneH-2,H-4), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H of oxteaneH-2, H-4), 4.71(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J11.5, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.97 (2H, s, CH ₂C₆H₄F), 3.40(3H, s, NCH₃), 3.09 (1H, br s, OH); ¹⁹F nmr (380 MHz, CDCl₃) δ−116.0;m/z: 502 [M+H]⁺ (found [M+H]⁺, 502.1787, C₂₉H₂₄FN₃O₅ requires [M+H]⁺502.1773).

(S)—N-(5-methyl-7-((3-methyloxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-127)

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyH-6), 7.59 (1H, d, J 2.5 Hz, pyH-3), 7.42-7.38 (2H, m, 2H ofC₆H₅), 7.26-7.21 (3H, m, 1H of C₆H₅, oxobenzoxazapineH-6, H-8), 7.10(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.06-7.04 (2H, m, 2H of C₆H₅),6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.01 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.90 (2H, d, J 5.5 Hz, 2H of oxetaneH-2, H-4),4.69 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.46 (2H, d, J5.5 Hz, 2H of oxetaneH-2, H-4), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapine), 3.41 (3H, s, NCH₃), 1.70 (3H, s, CCH₃); ¹³C nmr (100MHz, CDCl₃) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.9, 136.2,130.7, 130.3, 126.3, 125.7, 123.0, 120.7, 120.6, 114.4, 110.6, 92.7,82.9, 82.0, 77.2, 49.3, 35.4, 33.7, 25.4; m/z: 484 [M+H]⁺ (found [M+H]⁺,484.1855, C₂₈H₂₅N₃ 05 requires [M+H]⁺484.1817).

(S)—N-(7-((3-methoxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-128)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.42 (2H, dd, J 8.0, 7.5 Hz,2H of C₆H₅), 7.35-7.32 (2H, m, 2H of C₆H₅, oxobenzoxazapineH-6, or H-8),7.27-7.23 (1H, m, 1H of C₆H₅, oxobenzoxazapineH-6, or H-8), 7.16 (1H, d,J 9.0 Hz, oxobenzoxazapineH-9), 7.07 (2H, dd, J 8.5, 1.0 Hz, 2H ofC₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.85 (2H, d, J 6.5 Hz, 2H of oxetaneH-2, H-4),4.76 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.72 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.44 (3H, s, NCH₃ or OCH₃), 3.42 (3H, s, NCH₃ orOCH₃); m/z: 500 [M+H]⁺.

(S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-129)

¹H nmr (400 MHz, CDCl₃) δ 8.56 (1H, d, J 7.0 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H ofC₆H₅), 7.36-7.34 (2H, m, oxobenzoxazapineH-6, H-8), 727-7.23 (1H, m, 1Hof C₆H₅), 7.17 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.5,7.5 Hz, oxbenzoxazapineH-3), 4.98 (2H, s, 2H of oxetaneH-2, H-4), 4.93(2H, s, 2H of oxetaneH-2, H-4), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.44 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CDCl₃)δ−140.8 (quintet, J 20.5 Hz); m/z: 488 [M+H]⁺ (found [M+H]⁺, 488.1627,C₂₇H₂₂FN₃O₅ requires [M+H]⁺488.1616).

(S)-3-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl(3-morpholinopropyl)carbamate (I-130)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.0 Hz, NHCH), 8.43 (1H, d, J5.5 Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.34-7.32 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1Hof C₆H₅), 7.13 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.08-7.05 (2H, m,2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 6.23 (1H, t, J 5.5 Hz,CONHCH₂), 5.01 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.97 (2H,d, J 7.5 Hz, 2H of oxetaneH-2, H-4), 4.89 (2H, d, J 7.5 Hz, 2H ofoxetaneH-2, H-4), 4.71 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.72, 3.71 (4H, 2d AB system, J 4.5 Hz, 4H ofmorpholine), 3.43 (3H, s, NCH₃), 3.31 (2H, q, J 6.0 Hz, CONHCH₂CH₂CH₂N), 2.48-2.44 (6H, m, 4H of morpholine, CONHCH₂CH₂CH ₂N), 1.70(2H, quintet, J 6.0 Hz, CONHCH₂CH ₂CH₂N); m/z: 678 [M+Na]⁺, 656 [M+H]⁺,329 [M+H]²⁺ (found [M+H]⁺, 656.2740, C₃₅H₃₇N₅O₈ requires[M+H]⁺656.2465).

(S)—N-(7-((4-hydroxy-1-(4-phenoxypicolinoyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-131)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, 1×pyH-6), 8.42 (1H, d, J 5.5 Hz, 1×pyH-6), 7.61 (1H, d, J 2.5 Hz,1×pyH-3), 7.45-7.39 (4H, m, 2×2H of C₆H₅), 7.28-23 (4H, m, 2×1H of C₆H₅,oxobenzoxazapineH-6, H-8), 7.14-7.05 (6H, m, 2×2H of C₆H₅, 1×pyH-5,oxobenzoxazapineH-9), 6.94 (1H, dd, J 5.5, 2.5 Hz, 1×pyH-5), 6.88 (1H,dd, J 5.5, 2.5 Hz, 1×pyH-5), 5.03 (1H, dt, J Hz, oxobenzoxazapineH-3),4.71 (1H, dd, J Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J Hz, 1Hof oxobenzoxazapineH-2), 4.14-4.10 (1H m, 1H of piperidineH-2, H-6),3.83-3.76 (1H, m, 1H of piperidineH-2, H-6), 3.75-3.66 (1H, m, 1H ofpiperidineH-2, H-6), 3.60-3.53 (1H, m, 1H of piperidineH-2, H-6), 3.43(3H, s, NCH₃), 2.48-2.43 (1H, m, 1H of piperidineH-3, H-5), 2.16-2.03(1H, m, 1H of piperidineH-3, H-5), 1.98-1.85 (2H, m, 2H ofpiperidineH-3, H-5); m/z: 710 [M+H]⁺, 692 [M+H—H₂O]⁺ (found [M+H]⁺,710.2552, C₄₁H₃₅N₅O₇ requires [M+H]⁺710.2609).

(S)—N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-132)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 6.0Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.30-7.23 (3H, m, oxobenzoxazapineH-6, H-8, 1H of C₆H₅), 7.13(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 3.19-3.13 (2H, m, 2H ofpiperidineH-2, H-6), 3.04-2.95 (2H, m, 2H of piperidineH-2, H-6),2.14-2.04 (2H, m, 2H of piperidineH-3, H-5), 1.88-1.82 (2H, m, 2H ofpiperidineH-3, H-5); m/z: 513 [M+H]⁺, 495 [M+H—H₂O]⁺ (found [M+H]⁺,513.xxxx, C₂₉H₂₈N₄O₅ requires [M+H]⁺ 513.xxxx).

(S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-133)

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5Hz, pyH-6), 7.55 (1H, d, J 2.5 Hz, pyH-3), 7.28-7.25 (2H, m, 2H ofoxobenzoxazapineH-6, H-8), 7.11-7.07 (3H, m, oxobenzoxazapineH-9, 2H ofC₆H₄F), 7.04-7.01 (2H, m, 2H of C₆H₄F), 6.91 (1H, dd, J 5.5, 2.5 Hz,pyH-5), 5.01 (1H, dt, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.68 (1H,dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.28 (1H, dd, J 11.5, 9.5Hz, 1H of oxobenzoxazapineH-2), 3.40 (3H, s, NCH₃), 3.11-3.06 (2H, m, 2Hof piperidineH-2, H-6), 2.94-2.87 (2H, m, 2H of piperidineH-2, H-6),2.04-1.97 (2H, m, 2H of piperidineH-3, H-5), 1.79-1.72 (2H, m, 2H ofpiperidineH-3, H-5); ¹³C nmr (100 MHz, CDCl₃) δ 168.9, 166.1, 163.6,160.1 (d, J 245.0 Hz), 151.4, 150.2, 150.1, 149.5 (d, J 2.5 Hz), 136.3,130.9, 126.5, 123.1, 122.3 (d, J 8.5 Hz), 120.2, 117.0 (d, J 23.5 Hz),114.2, 110.3, 93.0, 83.3, 77.1, 67.0, 49.3, 43.5, 40.4, 35.4; ¹⁹F nmr(380 MHz, CDCl₃) δ−116.5; m/z: 531 [M+H]⁺ (found [M+H]⁺, 531.2031,C₂₉H₂₇FN₄O₅ requires [M+H]⁺531.2038).

(S)—N-(7-((l-acetyl-4-hydroxypiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorophenoxy)picolinamide(I-134)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyridineH-6), 7.57 (1H, d, J 2.5 Hz, pyridineH-3), 7.29-7.28 (2H, m,2H of oxobenzoxazapineH-6, H-8), 7.14 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 7.11-7.08 (2H, m, 2H of C₆H₄F), 7.07-7.02 (2H, m,2H of C₆H₄F), 6.92 (1H, dd, J 5.5, 2.5 Hz, pyridineH-5), 5.03 (1H, dt, J11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.05-3.98 (1H, m, 1H of piperidineH-2, H-6),3.74-3.68 (1H, m, 1H of piperidineH-2, H-6), 3.54-3.44 (2H, m, 2H ofpiperidineH-2, H-6), 3.43 (3H, s, NCH₃), 2.12 (3H, s, COCH₃), 2.09-1.98(2H, m, 2H of piperidineH-3, H-5), 1.89-1.78 (2H, m, 2H ofpiperidineH-3, H-5); ¹⁹F nmr (380 MHz, CDCl₃) δ−116.5; m/z: 573 [M+H]⁺(found [M+H]⁺, 573.2153, C₃₁H₂₉FN₄O₆ requires [M+H]⁺573.2144).

(S)-4-(4-fluorophenoxy)-N-(7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-135)

¹H nmr (400 MHz, CDCl₃) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.56 (1H, d, J 2.5 Hz, pyH-3), 7.30-7.28 (2H, m,oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),7.12-7.08 (2H, m, 2H of C₆H₄F), 7.05-7.02 (2H, m, 2H of C₆H₄F), 6.92(1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.29 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, CONCHS), 2.74-2.66 (2H, m, 2H ofpiperidineH-2, H-6), 2.46-2.39 (2H, m, 2H of piperidineH-2, H-6), 2.32(3H, s, NCH₃), 2.09-2.02 (2H, m, 2H of piperidineH-3, H-5), 1.94 (2H,ddd, J 13.0, 9.0, 3.5 Hz, 2H of piperidineH-3, H-5); ¹⁹F nmr (380 MHz,CDCl₃) δ−116.6; m/z: 545 [M+H]⁺ (found [M+H]⁺, 545.2199, C₃₀H₂₉FN₄O₅requires [M+H]⁺545.2195).

(S)—N-(7-((3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-136)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.31-7.29 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.22 (1H, m, 1Hof C₆H₅), 7.13 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 7.08-7.05 (2H, m,2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5,7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.05 (2H, d, J 9.0 Hz, 2H of azetidine-2, H-4),3.83 (2H, d, J 9.5 Hz, 2H of ozetidineH-2, H-4), 3.42 (3H, s, NCH₃);m/z: 485 [M+H]⁺ (found [M+H]⁺, 485.xxxx, C₂₇H₂₄N₄ 05 requires [M+H]⁺485.xxxx).

(S)—N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-137)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.32-7.29 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1Hof C₆H₅), 7.13 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.02 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J Hz, 11.5, 10.0 H ofoxobenzoxazapineH-2), 3.70 (2H, br d, J 9.5 Hz, 2H of azetidineH-2,H-4), 3.44 (2H, d, J 9.0 Hz, 2H of azetidineH-2, H-4), 3.41 (3H, s,CONCHS), 2.43 (3H, s, NCH₃); m/z: 499 [M+H]⁺ (found [M+H]⁺, 499.xxxx,C₂₈H₂₆N₄O₅ requires [M+H]⁺499.xxxx).

(S)-4-(4-fluorophenoxy)-N-(5-methyl-7-(5-(methylamino)-3-methylenepent-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-138)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.0 Hz, NH), 8.45 (1H, d, J 5.5Hz, pyH-6), 7.57 (1H, d, J 2.5 Hz, pyH-3), 7.32-7.29 (2H, m,oxobenzoxazapineH-6, H-8), 7.14 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9),7.11 (2H, t, J 8.0 Hz, 2H of C₆H₄F), 7.06-7.03 (2H, m, 2H of C₆H₄F),6.93 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.51 (1H, d, J 2.0 Hz, 1H of CH₂═),5.41 (1H, d, J 2.0 Hz, 1H of CH₂═), 5.03 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.44 (3H, s, CONCHS), 2.87 (2H, t, J 7.0 Hz, 2H ofCCH₂CH₂N), 2.49 (3H, s, NCH₃), 2.47 (2H, t, J 6.5 Hz, 2H of CCH₂CH₂N);¹³C nmr (100 MHz, CDCl₃) δ 168.9, 166.2, 163.6, 160.1 (d, J 245.0 Hz),151.4, 150.2, 150.0, 149.5, 136.3, 130.8, 128.9, 126.4, 123.5, 123.1,122.4 (d, J 8.5 Hz), 120.7, 117.0 (d, J 24.0 Hz), 114.2, 110.3, 89.8,88.0, 77.2, 49.9, 49.4, 37.2, 36.2, 35.4; ¹⁹F nmr (380 MHz, CDCl₃)δ−116.6; m/z: 515 [M+H]⁺ (found [M+H]⁺, 515.xxxx, C₂₉H₂₇FN₄O₄ requires[M+H]⁺515).

(S)—N-(7-((3-hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-143)

¹H nmr (400 MHz, CD₃OD) δ 8.50 (1H, d, J 5.5 Hz, pyH-6), 7.59 (1H, d, J2.0 Hz, pyH-3), 7.49-7.42 (4H, m, 2H of C₆H₅, oxobenzoxazapineH-6, H-8),7.30 (1H, tt, J 7.5, 1.0 Hz, 1H of C₆H₅), 7.24 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 7.14-7.11 (2H, m, 2H of C₆H₅), 7.07 (1H, dd, J5.5, 2.5 Hz, pyH-5), 4.98 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3),4.62 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.42 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.20 (2H, d, J 7.0 Hz, 2H ofazetidineH-2, H-4), 4.15 (2H, d, J 7.5 Hz, 2H of azetidineH-2, H-4),3.41 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CD₃OD) δ−138.2 (pentet, J 17.5Hz); m/z: 487 [M+H]⁺.

(S)—N-(74(3-fluoro-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-146)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.44 (1H, d, J 6.0Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H ofC₆H₅), 7.35-7.33 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1Hof C₆H₅), 7.15 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.95 (1H, dd, J 6.0, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.5,7.5 Hz, oxobenzoxazapineH-3), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.30 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.79 (2H, dd, J 15.0, 10.0 Hz, 2H of azetidineH-2,H-4), 3.56 (2H, dd, J 19.5, 10.0 Hz, 2H of azetidineH-2, H-4), 3.43 (3H,s, CONCHS), 2.47 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CDCl₃) δ−139.9; m/z:501 [M+H]⁺.

(S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoicacid (I-147)

¹H nmr (400 MHz, D₆-acetone) δ 8.79 (1H, d, J 7.0 Hz, NH), 8.54 (1H, d,J 5.5 Hz, pyH-6), 7.57 (1H, d, J 2.0 Hz, pyH-3), 7.53-7.49 (2H, m, 2H ofC₆H₅, 7.48 (1H, d, J 2.5 Hz, oxobenzoxazapineH-6), 7.39 (1H, dd, J 8.5,2.0 Hz, oxobenzoxazapineH-8), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H of C₆H₅),7.25 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.21-7.19 (2H, m, 2H ofC₆H₅), 7.11 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.97 (1H, dt, J 11.0, 7.5Hz, oxobenzoxazapineH-3), 4.88 (2H, d, J 7.5 Hz, 2H of oxetaneH-2, H-4),4.83 (2H, d, J 7.5 Hz, 2H of oxetaneH-2, H-4), 4.68 (1H, dd, J 9.5, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.40 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.44 (3H, s, NCH₃), 2.72-2.65 (4H, m, COCH ₂CH₂CO₂H); m/z: 586 [M+H]⁺.

(S)—N-(7-((3-hydroxy-1-(2,2,2-trifluoroacetyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-151)

¹H nmr (400 MHz, CDCl₃) δ 8.87 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.40 (2H, m, 2H ofC₆H₅), 7.31-7.23 (3H, m, 1H of C₆H₅, 2H of oxobenzoxazapineH-6, H-8,H-9), 7.17-7.14 (1H, m, 1H of oxobenzoxazapineH-6, H-8, H-9), 7.08-7.05(2H, m, 2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt,J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.72-4.68 (2H, m, 1H ofoxobenzoxazapineH-2, 1H of azetidineH-2, H-4), 4.54 (1H, d, J 10.0 Hz,1H of azetidineH-2, H-4), 4.48 (1H, dd, J 11.0, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (2H, q, J 10.0 Hz, 2H of azetidineH-2, H-4),3.42 (3H, s, NCH₃); ¹⁹F nmr (380 MHz, CDCl₃) δ−72.6; m/z: 581 [M+H]⁺.

(S)-4-cyclobutoxy-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (I-152)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.37 (1H, d, J 6.0Hz, pyH-6), 7.48 (1H, d, J 2.5 Hz, pyH-3), 7.28-7.26 (2H, m,oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.82 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.74 (1H, pentet, J 7.5 Hz, cBuH-1), 4.76-4.69(1H, m, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 2.52-2.44 (2H, m, 2H ofcBuH-2, H-4), 2.22-2.12 (2H, m, 2H of cBuH-2, H-4), 1.92-1.84 (1H, m, 1Hof cBuH-3), 1.75-1.70 (1H, m, cBuH-3); m/z: 450 [M+H]⁺.

(S)-4-cyclobutoxy-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-153)

¹H nmr (400 MHz, CDCl₃) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.37 (1H, d, J 6.0Hz, pyH-6), 7.49 (1H, d, J Hz, pyH-5), 7.32-7.29 (2H, m,oxobenzoxazapineH-6, H-8), 7.15 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.83 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.05 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, ddd, J 6.5, 3.5, 0.5 Hz, 2H ofoxetaneH-2, H-4), 4.80-4.78 (2H, m, 2H of oxetaneH-2, H-4), 4.76-4.70(2H, m, 1H of oxobenzoxazapineH-2, cBuH-1), 4.32 (1H, dd, J 11.0, 10.0Hz, 1H of oxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 2.52-2.44 (2H, m, 2Hof cBuH-2, H-4), 2.22-2.12 (2H, m, 2H of cBuH-2, H-4), 1.92-1.85 (1H, m,1H of cBuH-3), 1.77-1.67 (1H, m, 1H of cBuH-3); m/z: 464 [M+H]⁺.

(S)—N-(7-((3-methoxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-154)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.43-7.39 (2H, m, 2H ofC₆H₅), 7.34-7.31 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.7.23 (1H, m,1H of C₆H₅), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.07 (2H, dd,J 8.0, 1.0 Hz, 2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.71 (1H, dd, J 10.0, 7.5Hz, 1H of oxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.02-3.82 (4H, br s, azetidineH-2, H-4), 3.43 (3H,s, NCH₃ or OCH₃), 3.39 (3H, s, NCH₃ or OCH₃); m/z: 499 [M+H]⁺.

(S)—N-(7-((3-methoxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-155)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, dd, J5.5, 0.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2Hof C₆H₅), 7.37 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6), 7.36 (1H, dd, J8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.27-7.23 (1H, m, 1H of C₆H₅), 7.15(1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C₆H₅),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.05 (2H, br d, J 8.0 Hz, 2H of azetidineH-2,H-4), 3.60 (2H, d, J 9.0 Hz, 2H of azetidineH-2, H-4), 3.44 (3H, s, OCH₃or CONCH₃), 3.42 (3H, s, OCH₃ or CONCH3), 2.70 (3H, s, NCH3); m/z: 513[M+H]⁺.

(S)-4-(cyclopentyloxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-156)

¹H nmr (400 MHz, CDCl₃) δ 8.88 (1H, d, J 7.5 Hz, NH), 8.36 (1H, d, J 5.5Hz, pyH-6), 7.56 (1H, d, J 2.5 Hz, pyH-3), 7.28-7.26 (2H, m,oxobenzoxazapineH-6, H-8), 7.12 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.86 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.05 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.88-4.85 (1H, m, cPentaneH-1), 4.72 (1H, dd, J9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.30 (1H, dd, J 11.0, 9.5 Hz,1H of oxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 1.98-1.89 (2H, m, 2H ofcPentaneH-2, H-5), 1.86-1.73 (4H, m, 4H of cPentaneH-2, H-3, H-4, H-5),1.68-1.65 (2H, m, 2H of cPentaneH-2, H-3, H-4, H-5), 1.62 (6H, s, C(CH₃)₂OH); m/z: 464 [M+H]⁺.

(S)-4-(cyclopentyloxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide(I-157)

¹H nmr (400 MHz, CDCl₃) δ 8.88 (1H, d, J 7.0 Hz, NH), 8.36 (1H, d, J 5.5Hz, pyH-6), 7.56 (1H, d, J 2.5 Hz, pyH-3), 7.33-7.30 (2H, m,oxobenzoxazapineH-6, H-8), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.87 (1H, dd, J 6.0, 2.5 Hz, pyH-5), 5.06 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.93 (2H, br d, J 6.5 Hz, 2H of oxetaneH-2, H-4),4.88-4.85 (1H, m, cPentaneH-1), 4.80 (2H, d, J 6.5 Hz, oxetaneH-2, H-4),4.72 (1H, dd, J 9.5, 6.5 Hz, 1H of oxobenzoxazapineH-2), 4.33 (1H, dd, J11.5, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.43 (3H, s, NCH₃), 1.99-1.89(2H, m, 2H of cPentaneH-2, H-5), 1.86-1.75 (4H, m, 4H of cPentaneH-2,H-3, H-4, H-5), 1.66-1.62 (2H, m, 2H of cPentaneH-2, H-3, H-4, H-5);m/z: 478 [M+H]⁺.

Methyl(S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolate(I-159)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5Hz, pyH-6), 7.60 (1H, d, J 2.5 Hz, pyH-3), 7.46-7.39 (4H, m, 2H of C₆H₅,oxobenzoxazapineH-6, H-8), 7.24 (1H, tt, J 7.5, 1.5 Hz, 1H of C₆H₅),7.19 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.07-7.05 (2H, m, 2H ofC₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-3), 5.03 (1H, dt, J 11.5, 7.5Hz, oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.34 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.84 (3H, s, OCH₃), 3.42 (3H, s, NCH₃); m/z: 472[M+H]⁺.

3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-ylL-valinate (I-160)

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H ofC₆H₅), 7.31-7.27 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H, m, 1Hof C₆H₅), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.05-4.97 (3H, m,oxobenzoxazapineH-3, 2H of oxetaneH-2, H-4), 4.89 (2H, t, J 7.0 Hz, 2Hof oxetaneH-2, H-4), 4.71 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, t, J 11.0 Hz, 1H ofoxobenzoxazapineH-2), 3.42 (3H, s, NCH₃), 3.42-3.39 (1H, m, COCHNH₂),2.18-2.09 (1H, m, CH(CH₃)₂), 1.04 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH ₃)₂),0.99 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH₃)₂); m/z: 585 [M+H]⁺.

(S)-3-(5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propiolicacid (I-161)

¹H nmr (400 MHz, CD₃OD) δ 8.47 (1H, d, J 6.0 Hz, pyH-6), 7.56 (1H, d, J2.0 Hz, oxobenzoxazapineH-6), 7.50 (1H, d, J 2.5 Hz, pyH-3), 7.47-7.41(3H, m, 2H of C₆H₅, oxobenzoxazapineH-8), 7.28 (1H, br t, J 7.5 Hz, 1Hof C₆H₅), 7.20 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.11-7.09 (2H, m,2H of C₆H₅), 7.04 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.98 (1H, dd, J 11.5,7.5 Hz, oxobenzoxazapineH-3), 4.63 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.38 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.41 (3H, s, NCH₃); m/z: 458 [M+H]⁺.

3-4(S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-ylL-valinate benzenesulfonic acid salt (I-164)

¹H nmr (400 MHz, CDCl₃) δ 9.06 (1H, d, J 7.0 Hz, NH), 8.62 (1H, d, J 6.0Hz, pyH-6), 8.40 (2H, br s, NH₂), 7.85 (2H, d, J Hz, 2H of C₆H₅SO₃H),7.66 (1H, br s, pyH-3), 7.43 (2H, t, J 8.0 Hz, 2H of C₆H₅), 7.38-7.22(H, 1H of C₆H₅, 3H of C₆H₅SO₃H, oxobenzoxazapineH-6, H-8, H-9), 7.06(2H, d, J 8.5 Hz, 2H of C₆H₅), 7.02 (1H, br d, J 4.0 Hz, pyH-5), 4.97(1H, dt, J 11.5, 6.5 Hz, oxobenzoxazapineH-3), 4.93-4.84 (4H, m,oxetaneH-2, H-4), 4.59 (1H, br dd, J 10.0, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.44 (1H, br dd, J 10.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 4.03 (1H, br s, COCHNH₂), 3.28 (3H, s, NCH₃),2.36-2.28 (1H, m, CHCH(CH₃)₂), 1.05-1.02 (6H, m, CH(CH ₃)₂); m/z: 585[M+H]⁺.

(S)-4-((3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-yl)oxy)-4-oxobutanoicacid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (I-165)

¹H nmr (400 MHz, D6-DMSO) δ 8.87 (1H, d, J 8.0 Hz, NH), 8.56 (1H, d, J6.0 Hz, pyH-6), 7.60 (1H, d, J 2.0 Hz, pyH-3), 7.51-7.46 (2H, m, 2H ofC₆H₅), 7.36 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.33-7.30 (2H,m, 1H of C₆H₅, oxobenzoxazapineH-6), 7.23 (1H, d, J 8.0 Hz,oxobenzaxazapineH-9), 7.21-7.18 (3H, m, 2H of C₆H₅, pyH-5), 4.85 (2H, d,J 7.5 Hz, 2H of oxetaneH-2, H-4), 4.81 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 4.78 (2H, d, J 7.5 Hz, 2H of oxetaneH-2, H-4),4.57 (1H, dd, J 11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.45 (1H, dd,J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 3.42-3.16 (6H, br s,C(CH₂OH)₃), 3.30 (3H, s, NCH₃), 2.56 (2H, dd, J 7.0, 6.0 Hz, 2H ofCOCH₂CH₂CO), 2.43 (2H, dd, J 7.0, 6.0 Hz, 2H of COCH₂CH₂CO); m/z: 586[M+H]⁺.

(S)—N-(7-((3-fluoro-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-166)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.42 (2H, dd, J 8.0, 7.5 Hz,2H of C₆H₅), 7.35-7.33 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.23 (1H,m, 1H of C₆H₅), 7.14 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.07 (2H,d, J 7.5 Hz, 2H of C₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H,dt, J Hz, oxobenzoxazapineH-3), 4.72 (1H, dd, J Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J Hz, 1H of oxobenzoxazapineH-2),3.73 (2H, dd, J 15.5, 9.0 Hz, 2H of azetidineH-2, H-4), 3.53 (2H, dd, J20.5, 9.5 Hz, 2H of azetidineH-2, H-4), 3.43 (3H, s, NCH₃), 2.45 (1H, q,J 6.0 Hz, NCH(CH₃)₂), 0.99 (6H, d, J 6.0 Hz, CH(CH₃)₂); ¹⁹F nmr (380MHz, CDCl₃) δ−139.3; m/z: 529 [M+H]⁺.

(S)—N-(7-((3-fluoro-1-(2,2,2-trifluoroethyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-168)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H, m, 2H ofC₆H₅), 7.35-7.33 (2H, m, oxobenzoxazapineH-6, H-8), 7.27-7.24 (1H, m, 1Hof C₆H₅), 7.16 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m,2H of C₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.72 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazapineH-2), 4.32 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.94 (2H, dd, J 16.5, 9.5 Hz, 2H of azetidineH-2,H-4), 3.88 (2H, dd, J 10.0, 9.5 Hz, 2H of azetidineH-2, H-4), 3.44 (3H,s, NCH₃), 3.15 (2H, q, J 9.0 Hz, NCH₂CF₃); ¹⁹F nmr (380 MHz, CDCl₃)δ−71.0, −138.8; m/z: 569 [M+I-1]⁺.

(S)—N-(7-((1-(cyclopropylmethyl)-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-169)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.0 Hz, NH), 8.44 (1H, d, J 5.5Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.39 (2H, m, 2H ofC₆H₅), 7.36-7.33 (2H, m, oxobenzoxazapineH-6, H-8), 7.28-7.24 (1H, m, 1Hof C₆H₅), 7.15 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 7.09-7.06 (2H, m,2H of C₆H₅), 6.95 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0,7.5 Hz, oxobenzoxazapineH-3), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.88-3.80 (2H, m, 2H of azetidineH-2, H-4), 3.62(2H, dd, J 9.5, 8.5 Hz, 2H of azetidineH-2, H-4), 3.43 (3H, s, NCH₃),2.48 (2H, d, J Hz, NCH2cPr), 0.89-0.84 (1H, cPrH-1), 0.53-0.48 (2H, m,2H of cPrH-2, H-3), 0.17-0.13 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (380MHz, CDCl₃) δ−139.1; m/z: 541 [M+H]⁺.

(S)-4-(4-fluorobenzyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-175)

¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.85 (t, J=0.9Hz, 1H), 7.45 (d, J=0.8 Hz, 1H), 7.34-7.27 (m, 2H), 7.18-7.08 (m, 3H),7.03-6.92 (m, 2H), 4.88 (dt, J=11.3, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.3Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 3.96 (dt, J=11.9, 4.5 Hz, 2H),3.78 (s, 2H), 3.72 (ddd, J=11.8, 8.9, 3.0 Hz, 2H), 3.43 (s, 3H), 2.14(s, 1H), 2.06-2.01 (m, 2H), 1.90 (ddd, J=13.0, 9.0, 3.9 Hz, 2H). ¹⁹F NMR(376 MHz, Chloroform-d) 6-116.72 (ddd, J=13.9, 8.9, 5.3 Hz). LC/MS:Purity 99%, MS (m/e) 519 (MH+).

(S)-4-(4-fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide(I-178)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85(q, J=0.9 Hz, 1H), 7.46 (d, J=0.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.08(m, 3H), 7.02-6.92 (m, 2H), 4.94 (d, J=6.9 Hz, 2H), 4.91-4.83 (m, 1H),4.80 (dd, J=6.6, 0.9 Hz, 2H), 4.70 (dd, J=9.8, 7.2 Hz, 1H), 4.33 (dd,J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.43 (s, 3H), 2.60 (s, 1H). LC/MS:Purity 94%, MS (m/e) 491 (M+H)⁺.

(S)-1-Benzyl-4-fluoro-N-(5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(I-179)

¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=6.8 Hz, 1H), 7.61-7.56 (m, 1H),7.50-7.44 (m, 2H), 7.37 (d, J=7.0 Hz, 4H), 7.22 (dd, J=12.4, 6.2 Hz,3H), 7.20-7.11 (m, 2H), 5.23 (s, 2H), 5.08 (dt, J=12.6, 7.0 Hz, 1H),4.81 (dd, J=9.7, 7.0 Hz, 1H), 4.29 (t, J=10.4 Hz, 1H), 3.45 (d, J=1.6Hz, 3H), 2.60 (d, J=1.6 Hz, 3H). HRMS (TOFMS ES+) exact mass C₂₉H₂₄FN₅O₃509.1863, found 510.1930.

(S)-1-Benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(I-181)

MS (ESI, m/e) Calculated 533.2438; Found 534.1 M+H]⁺.

(±)-4-Benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1-pyrazole-1-carboxamide(racemic version of I-182)

Route 1. ¹H NMR (400 MHz, Methanol-d₄) δ 7.87 (q, J=0.8 Hz, 1H), 7.51(s, 1H), 7.31-7.23 (m, 2H), 7.26-7.14 (m, 3H), 7.10 (d, J=8.1 Hz, 1H),6.45-6.35 (m, 2H), 4.38 (dd, J=11.4, 7.7 Hz, 1H), 3.82 (s, 2H), 3.66 (d,J=4.3 Hz, 8H), 3.37 (s, 3H), 2.74 (td, J=13.3, 7.6 Hz, 1H), 2.63-2.42(m, 2H), 2.15-1.98 (m, 1H), 1.87-1.80 (m, 4H). LC/MS: Purity 99%, MS(m/e) 500 (M+H)⁺.

(S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-184)

Route 2. ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.5 Hz, 1H), 7.85(q, J=0.9 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.17-7.08 (m, 2H), 7.07-6.92(m, 3H), 6.28 (dd, J=8.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 4.90 (dt,J=11.0, 7.5 Hz, 1H), 4.61 (dd, J=9.7, 7.6 Hz, 1H), 4.20 (dd, J=11.1, 9.8Hz, 1H), 3.78 (s, 2H), 3.71-3.61 (m, 8H), 3.40 (s, 3H), 1.86 (t, J=5.3Hz, 4H). LC/MS: Purity 97%, MS (m/e) 520 (M+H)⁺.

(S)-5-benzyl-N-(7-(3-chloro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-187)

¹H nmr (400 MHz, CDCl₃) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41-7.39 (2H, m,oxobenzoxazapineH-6, H-8), 7.29-7.22 (5H, m, C₆H₅), 7.15 (1H, d, J 9.0Hz, oxobenzoxazapineH-9), 6.31 (1H, s, CH═CCl), 5.05 (1H, dt, J 11.5,7.5 Hz, oxobenzoxazapineH-3), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.43 (3H, s, NCH₃), 1.57(6H, s, C(CH₃)₂OH); ¹³C nmr (100 MHz, CDCl₃) δ 168.7, 158.9, 158.4,154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2,125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29.4; m/z: 480, 478[M+H—H₂O]⁺; m/z: 496, 494 [M−H]⁻ (found [M+H]⁺, 496.1743, C₂₅H₂₆ClN₅O₄requires [M+H]⁺496.1746).

(S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-188)

¹H nmr (400 MHz, CDCl₃) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28-7.20 (7H, m,oxobenzoxazapineH-6, H-8, C₆H₅), 7.09 (1H, d, J 9.0 Hz,oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.14 (2H, s, CH ₂C₆H₅), 3.62 (2H, s, CCH₂N), 3.38(3H, s, NCH₃), 2.73-2.70 (4H, m, 4H of pyrrolidine), 1.86-1.82 (4H, m,4H of pyrrolidine); m/z: 485 [M+H]⁺ (found [M+H]⁺, 485.2322, C₂₇H₂₈N₆ 03requires [M+H]⁺ 485.2296).

(S)-5-benzyl-N-(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-189)

¹H nmr (400 MHz, CDCl₃) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29-7.7.27 (2H,m, oxobenzoxazapineH-6, H-8), 7.25-7.18 (5H, m, C₆H₅), 7.10 (1H, d, J9.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dt, J 11.0, 7.0 Hz,oxobenzoxazapineH-3), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.27 (1H, t, J 10.5 Hz, 1H ofoxobenzoxazapineH-2), 4.13 (2H, s, CH ₂C₆H₅), 3.78, 3.76 (4H, 2d ABsystem, J 4.5 Hz, 4H of morpholine), 3.50 (2H, s, CCH₂N), 3.39 (3H, s,NCH₃), 2.65, 2.63 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine); m/z:501 [M+H]⁺ (found [M+H]⁺, 501.2245, C₂₇H₂₈N₆O₄ requires [M+H]⁺501.2245).

(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(phenoxy-d5)picolinamide(I-190)

¹H nmr (400 MHz, CDCl₃) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44 (1H, d, J 6.0Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.32-7.29 (2H, m,oxobenzoxazapineH-6, H-8), 7.14 (1H, d, J 9.0 Hz, oxobenzoxazapineH-9),6.94 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.03 (1H, dt, J 11.0, 7.5 Hz,oxobenzoxazapineH-3), 4.92 (2H, dd, J 6.5, 4.0 Hz, 2H of oxetaneH-2,H-4), 4.78 (2H, dd, J 6.5, 1.0 Hz, 2H of oxetaneH-2, H-4), 4.71 (1H, dd,J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.31 (1H, dd, J 11.0, 9.5 Hz,1H of oxobenzoxazapine), 3.42 (3H, s, NCH₃), 3.16 (1H, s, OH); m/z: 491[M+H]⁺ (found [M+H]⁺, 491.xxxx, C₂₇H₁₈D₅N₃O₆ requires [M+H]⁺491.1973).

(S)—N-(7-((1-acetyl-3-fluoroazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-191)

3-(((S)-5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-ylL-alaninate trifluoroacetic acid salt (I-194)

(S)—N-(7-((3-hydroxy-1-isopropylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-195)

(S)—N-(7-((1-(cyclopropylmethyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-196)

(S)—N-(7-((1-acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-197)

(S)—N-(7-((1-(ethylcarbamoyl)-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-198)

(S)-3-((5-methyl-4-oxo-3-(4-phenoxypicolinamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)oxetan-3-ylethylcarbamate (I-199)

(S)—N-(7-((3-hydroxy-1-neopentylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-200)

(S)—N-(5-methyl-7-((1-methyl-1H-imidazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-203)

(S)—N-(7-(3-(butylamino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-204)

(S)—N-(7-(3-((4-fluorobenzyl)amino)-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-205)

(S)-4-Benzyl-N-(7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-212)

Route 1. ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.86(q, J=0.8 Hz, 1H), 7.46 (s, 1H), 7.33-7.14 (m, 7H), 7.13-7.06 (m, 1H),4.86 (dt, J=11.2, 7.3 Hz, 1H), 4.67 (dd, J=9.7, 7.3 Hz, 1H), 4.34-4.24(m, 1H), 3.81 (s, 2H), 3.42 (s, 3H), 1.32 (s, 9H). LC/MS: Purity 99%, MS(m/e) 457 (M+H)⁺.

(S)-4-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-213)

Route 1. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86(q, J=0.9 Hz, 1H), 7.47 (d, J=0.9 Hz, 1H), 7.33-7.25 (m, 4H), 7.25-7.09(m, 4H), 4.87 (dt, J=11.2, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.3 Hz, 1H),4.31 (dd, J=11.3, 9.8 Hz, 1H), 3.81 (s, 2H), 3.42 (s, 3H), 1.63 (s, 6H).

LC/MS: Purity 99%, MS (m/e) 459 (M+H)⁺.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (I-214)

Route 3. ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.78 (s, 1H),8.60-8.51 (m, 1H), 7.94-7.84 (m, 3H), 7.53-7.47 (m, 2H), 7.49-7.42 (m,2H), 7.37 (dd, J=8.0, 5.0 Hz, 1H), 7.34-7.26 (m, 2H), 7.22 (t, J=7.9 Hz,3H), 4.91 (dt, J=11.2, 7.1 Hz, 1H), 4.73 (ddd, J=9.8, 7.2, 0.9 Hz, 1H),4.34 (app ddd, J=10.9, 9.8, 0.9 Hz, 1H), 3.84 (s, 2H), 3.45 (s, 3H).

LC/MS: Purity 99%, MS (m/e) 478 (M+H)⁺.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-215)

Route 3. ¹H NMR (400 MHz, Methylene Chloride-d₂) 6 8.65-8.56 (m, 1H),7.91 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.72 (td, J=7.8, 1.8 Hz, 1H),7.60-7.44 (m, 4H), 7.36-7.15 (m, 7H), 4.91 (dt, J=11.3, 7.1 Hz, 1H),4.74 (dd, J=9.8, 7.2 Hz, 1H), 4.34 (dd, J=11.2, 9.8 Hz, 1H), 3.83 (s,2H), 3.45 (s, 3H).

LC/MS: Purity 96%, MS (m/e) 478 (M+H)⁺.

(S)-4-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-216)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86(q, J=0.9 Hz, 1H), 7.47 (d, J=0.9 Hz, 1H), 7.35-7.25 (m, 4H), 7.29-7.17(m, 1H), 7.21-7.12 (m, 3H), 4.97-4.83 (m, 3H), 4.80 (dt, J=6.5, 0.8 Hz,2H), 4.69 (dd, J=9.8, 7.3 Hz, 1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3.81(s, 2H), 3.42 (s, 3H), 2.92 (s, 1H).

LC/MS: Purity 99%, MS (m/e) 473 (M+H)⁺.

(S)-4-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-217)

Route 1. ¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=7.5 Hz, 1H), 7.86(t, J=0.9 Hz, 1H), 7.46 (s, 1H), 7.33-7.25 (m, 2H), 7.25-7.12 (m, 3H),7.03 (d, J=8.7 Hz, 1H), 6.28 (dd, J=8.7, 2.7 Hz, 1H), 6.21 (d, J=2.6 Hz,1H), 4.90 (dt, J=11.1, 7.6 Hz, 1H), 4.61 (dd, J=9.7, 7.6 Hz, 1H), 4.20(dd, J=11.0, 9.8 Hz, 1H), 3.81 (s, 2H), 3.73-3.60 (m, 8H), 3.40 (s, 3H),1.86 (t, J=5.2 Hz, 4H).

LC/MS: Purity 99%, MS (m/e) 502 (M+H)⁺.

(S)-4-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-218)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85(q, J=0.9 Hz, 1H), 7.45 (d, J=0.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.16-7.08(m, 3H), 7.02-6.92 (m, 2H), 4.87 (dt, J=11.2, 7.3 Hz, 1H), 4.73-4.64 (m,1H), 4.31 (dd, J=11.3, 9.7 Hz, 1H), 3.78 (s, 2H), 3.42 (s, 3H), 2.02 (s,1H), 1.63 (s, 6H).

LC/MS: Purity 99%, MS (m/e) 459 (M−H₂O+H)⁺.

(S)-4-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-219)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86(q, J=0.9 Hz, 1H), 7.47 (d, J=0.8 Hz, 1H), 7.34-7.25 (m, 4H), 7.25-7.17(m, 1H), 7.18 (dt, J=1.3, 0.6 Hz, 1H), 7.20-7.10 (m, 2H), 4.88 (dt,J=11.3, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.3 Hz, 1H), 4.32 (dd, J=11.3, 9.8Hz, 1H), 3.81 (s, 2H), 3.43 (s, 3H), 2.60-2.48 (m, 2H), 2.41-2.29 (m,2H), 2.25 (s, 1H), 1.97-1.82 (m, 2H).

LC/MS: Purity 99%, MS (m/e) 471 (M+H)⁺.

(S)-4-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide(I-220)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J=7.3 Hz, 1H), 7.75(d, J=1.0 Hz, 1H), 7.32-7.24 (m, 4H), 7.24-7.16 (m, 1H), 7.20-7.09 (m,3H), 4.88 (dt, J=11.3, 7.3 Hz, 1H), 4.68 (dd, J=9.8, 7.3 Hz, 1H), 4.31(dd, J=11.3, 9.8 Hz, 1H), 3.73 (s, 2H), 3.42 (s, 3H), 2.15 (app s, 3H),1.63 (s, 6H).

LC/MS: Purity 96%, MS (m/e) 473 (M+H)⁺.

(S)-4-(4-Fluorobenzyl)-N-(7-((l-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-221)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85(d, J=1.1 Hz, 1H), 7.45 (s, 1H), 7.31 (dq, J=4.6, 2.0 Hz, 2H), 7.17-7.09(m, 3H), 7.03-6.93 (m, 2H), 4.88 (dt, J=11.2, 7.2 Hz, 1H), 4.69 (dd,J=9.8, 7.3 Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.43(s, 3H), 2.60-2.49 (m, 1H), 2.57-2.50 (m, 2H), 2.36 (qd, J=9.2, 2.7 Hz,2H), 2.24 (br s, 1H), 1.96-1.85 (m, 2H).

LC/MS: Purity 99%, MS (m/e) 489 (M+H)⁺.

(S)-4-(4-Fluorobenzyl)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-222)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.85(q, J=0.9 Hz, 1H), 7.46 (d, J=0.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.08(m, 3H), 7.02-6.92 (m, 2H), 4.94 (d, J=6.9 Hz, 2H), 4.91-4.83 (m, 1H),4.80 (dd, J=6.6, 0.9 Hz, 2H), 4.70 (dd, J=9.8, 7.2 Hz, 1H), 4.33 (dd,J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.43 (s, 3H), 2.60 (s, 1H).

LC/MS: Purity 94%, MS (m/e) 491 (M+H)⁺.

(S)-3-(4-Fluorobenzyl)-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-223)

Route 3. ¹H NMR (400 MHz, Chloroform-0 6 8.04 7.97 (app m, 2H),7.35-7.28 (m, 2H), 7.24-7.16 (m, 2H), 7.20-7.11 (m, 1H), 7.04-6.93 (m,2H), 6.10 (d, J=2.7 Hz, 1H), 4.91 (dt, J=11.3, 7.2 Hz, 1H), 4.72 (dd,J=9.7, 7.3 Hz, 1H), 4.35 (dd, J=11.3, 9.7 Hz, 1H), 3.96 (s, 2H), 3.45(s, 3H), 2.60-2.49 (m, 2H), 2.36 (dt, J=12.2, 9.2 Hz, 2H), 1.97-1.82 (m,2H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−116.69 (ddd, J=14.2, 8.9, 5.4Hz).

LC/MS: Purity 97%, MS (m/e) 511 (M+Na)⁺.

(S)-4-(4-Fluorobenzyl)-N-(7-((2-hydroxyspiro[3.3]heptan-2-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-224)

Route 3. ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.84(q, J=0.9 Hz, 1H), 7.45 (d, J=0.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.17-7.07(m, 3H), 7.02-6.92 (m, 2H), 4.87 (dt, J=11.3, 7.3 Hz, 1H), 4.68 (dd,J=9.8, 7.3 Hz, 1H), 4.31 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.41(s, 3H), 2.66-2.57 (m, 2H), 2.39-2.29 (m, 2H), 2.20-2.12 (m, 3H), 2.05(dd, J=8.1, 6.9 Hz, 2H), 1.92-1.80 (m, 2H). ¹⁹F NMR (376 MHz,Chloroform-d) δ−116.74 (ddd, J=14.2, 8.7, 5.5 Hz).

LC/MS: Purity 94%, MS (m/e) 529 (M+H)⁺.

(S)-4-(4-Fluorobenzyl)-N-(7-((6-hydroxy-2-oxaspiro[3.3]heptan-6-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-225)

Route 3. ¹H NMR (400 MHz, Methylene Chloride-d₂) 6 7.87 (d, J=7.1 Hz,1H), 7.84 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.34-7.24 (m, 2H), 7.21-7.12(m, 3H), 7.04-6.93 (m, 2H), 4.85 (dt, J=11.2, 7.2 Hz, 1H), 4.76 (s, 2H),4.73-4.66 (m, 1H), 4.66 (s, 2H), 4.30 (dd, J=11.3, 9.8 Hz, 1H), 3.80 (s,2H), 3.39 (s, 3H), 2.84-2.74 (m, 2H), 2.55-2.46 (m, 2H). ¹⁹F NMR (376MHz, Methylene Chloride-d₂) 6-117.74 (ddd, J=14.3, 9.0, 5.4 Hz).

LC/MS: Purity 99%, MS (m/e) 531 (M+H)⁺.

(S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-228)

Route 1. ¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=7.3 Hz, 1H), 7.86(q, J=0.9 Hz, 1H), 7.47 (d, J=0.9 Hz, 1H), 7.39-7.33 (m, 2H), 7.33-7.14(m, 6H), 7.08 (dd, J=8.1, 0.8 Hz, 1H), 4.89 (dt, J=11.3, 7.3 Hz, 1H),4.72-4.63 (m, 1H), 4.35-4.25 (m, 1H), 3.81 (s, 2H), 3.42 (s, 3H).

LC/MS: Purity 99%, MS (m/e) 456 (M+H)⁺.

(S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide(I-229)

Route 2. ¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=7.3 Hz, 1H), 7.85(s, 1H), 7.45 (s, 1H), 7.39-7.32 (m, 2H), 7.16-7.04 (m, 3H), 6.97 (t,J=8.6 Hz, 2H), 4.89 (dt, J=11.2, 7.3 Hz, 1H), 4.67 (dd, J=9.8, 7.4 Hz,1H), 4.30 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.42 (s, 3H).

LC/MS: Purity 96%, MS (m/e) 474 (M+H)⁺.

(S)-4-Benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide(I-230)

Route 2. ¹H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=7.4 Hz, 1H), 7.75(d, J=1.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.31-7.24 (m, 2H), 7.23-7.16 (m,1H), 7.16-7.12 (m, 2H), 7.07 (d, J=8.4 Hz, 1H), 4.89 (dt, J=11.3, 7.4Hz, 1H), 4.66 (dd, J=9.8, 7.4 Hz, 1H), 4.30 (dd, J=11.3, 9.8 Hz, 1H),3.73 (s, 2H), 3.42 (s, 3H), 2.15 (s, 3H).

LC/MS: Purity 99%, MS (m/e) 470 (M+H)⁺.

(S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide(I-231)

Route 2. ¹H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J=7.4 Hz, 1H),7.51-7.46 (m, 1H), 7.38-7.30 (m, 2H), 7.12 (dd, J=8.3, 5.4 Hz, 2H), 7.06(d, J=8.4 Hz, 1H), 6.96 (t, J=8.5 Hz, 2H), 5.94 (s, 1H), 4.88 (dt,J=11.2, 7.3 Hz, 1H), 4.65 (dd, J=9.8, 7.3 Hz, 1H), 4.30 (app m, 1H),4.27 (s, 2H), 3.41 (s, 3H). LC/MS: Purity 94%, MS (m/e) 474 (M+H)⁺.

(S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide(I-232)

Route 2. ¹H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J=2.7 Hz, 1H), 7.97(d, J=7.3 Hz, 1H), 7.38-7.32 (m, 2H), 7.19 (app dddd, J=8.3, 5.3, 2.1,1.5 Hz, 2H), 7.08 (dd, J=8.4, 0.4 Hz, 1H), 7.01-6.93 (m, 2H), 6.10 (d,J=2.7 Hz, 1H), 4.91 (dt, J=11.3, 7.3 Hz, 1H), 4.69 (dd, J=9.8, 7.4 Hz,1H), 4.33 (dd, J=11.3, 9.8 Hz, 1H), 3.95 (s, 2H), 3.43 (s, 3H).

LC/MS: Purity 95%, MS (m/e) 474 (M+H)⁺.

(5)-5-benzyl-N-(7-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-233)

1H nmr (400 MHz, CD3OD) δ 7.52 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.39 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.32-7.23 (5H, m,C6H5), 7.21 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.02 (1H, dd, J11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.60 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.41 (1H, dd, J 11.5, 10.0, Hz, 1H ofoxobenzoxazapineH-2), 4.35 (2H, d, J 11.5 Hz, 2H of azetidineH-2, H-4),4.15 (2H, s, CH2C6H5), 4.14 (2H, m, 2H of azetidineH-2, H-4), 3.40 (3H,s, NCH3); m/z: 473 [M+H]+.

(S)-5-benzyl-N-(7-((3-hydroxy-1-methylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-234)

1H nmr (400 MHz, CD3OD) δ 7.55 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.39 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.33-7.24 (5H, m,C₆H₅), 7.22 (1H, d, J 8.0 Hz, oxobenzoxazapineH-9), 5.00 (1H, dd, J11.5, 7.5 Hz, oxobenzoxazapineH-3), 4.59 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.44 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 4.16 (2H, s, CH2C6H5), 4.15 (2H, d, J 9.5 Hz, 2Hof azetidineH-2, H-4), 3.81 (2H, d, J 10.0 Hz, 2H of azetidineH-2, H-4),3.39 (3H, s, CONCH3), 2.74 (3H, s, NCH3); m/z: 487 [M+H]+.

(S)—N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamide(I-237)

¹H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J=7.3 Hz, 1H), 7.87 (s, 1H),7.48 (d, J=0.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.15-7.03 (m, 2H), 6.84-6.74(m, 2H), 4.88 (dt, J=11.2, 7.3 Hz, 1H), 4.67 (dd, J=9.8, 7.4 Hz, 1H),4.29 (dd, J=11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.41 (s, 3H). ¹³C NMR (101MHz, Chloroform-d) δ 168.51, 162.57 (dd, J=116.5, 12.0 Hz),160.84-159.36 (m), 149.18 (d, J=5.4 Hz), 143.12, 137.56, 131.08 (dd,J=9.5, 6.1 Hz), 130.71, 126.89, 126.50, 124.58, 123.01-122.71 (m),122.62, 118.23, 111.42 (dd, J=21.1, 3.9 Hz), 104.08 (t, J=25.6 Hz),77.32, 50.15, 35.65, 23.33. ¹⁹F NMR (376 MHz, Chloroform-d) δ−112.35 (p,J=7.6 Hz), −113.80 (q, J=8.5 Hz). LCMS: Purity 97%, MS (m/z) 491/493(M+H)⁺.

(S)-4-(2,4-Difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-238)

¹H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J=7.2 Hz, 1H), 7.86 (s, 1H),7.46 (s, 1H), 7.24 (d, J=7.4 Hz, 2H), 7.12-7.04 (m, 2H), 6.77 (t, J=8.4Hz, 2H), 4.85 (dt, J=11.2, 7.3 Hz, 1H), 4.65 (dd, J=9.8, 7.3 Hz, 1H),4.29 (dd, J=11.3, 9.8 Hz, 1H), 3.75 (s, 2H), 3.38 (s, 3H), 1.59 (s, 6H).¹³C NMR (101 MHz, Chloroform-d) δ 168.41, 162.40 (dd, J=115.8, 11.9 Hz),159.94 (dd, J=116.6, 11.8 Hz), 149.80, 149.02, 142.97, 135.99,131.11-130.79 (m), 126.79, 126.49, 123.04, 122.73 (dd, J=16.0, 3.8 Hz),122.44, 120.49, 111.26 (dd, J=21.0, 3.8 Hz), 103.90 (t, J=25.6 Hz),94.77, 80.46, 65.45, 49.98, 35.50, 31.38, 23.15. ¹⁹F NMR (376 MHz,Chloroform-d) δ−112.33 (p, J=7.7 Hz), −113.78 (q, J=8.4 Hz). LCMS:Purity 95%, MS (m/z) 495 (M+H)⁺.

(S)-4-(2,4-Difluorobenzyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide(I-239)

¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.87 (s, 1H),7.47 (s, 1H), 7.30-7.20 (m, 2H), 7.15-7.03 (m, 2H), 6.86-6.75 (m, 2H),4.85 (dt, J=11.2, 7.3 Hz, 1H), 4.67 (dd, J=9.8, 7.3 Hz, 1H), 4.29 (dd,J=11.3, 9.8 Hz, 1H), 3.77 (s, 2H), 3.50 (s, 2H), 3.41 (s, 3H), 1.30 (s,6H). ¹³C NMR (101 MHz, Chloroform-d) δ 168.41, 160.61, 149.59, 148.99,142.94, 135.95, 131.03, 130.99-130.69 (m), 126.75, 126.56, 122.98,122.89-122.56 (m), 122.43, 121.05, 111.27 (dd, J=21.1, 3.8 Hz), 103.93(t, J=25.6 Hz), 95.38, 80.45, 77.16, 71.55, 49.98, 35.51, 34.81, 25.40,23.19. ¹⁹F NMR (376 MHz, Chloroform-d) δ−112.39 (p, J=7.7 Hz), −113.81(q, J=8.4 Hz). LCMS: Purity 96%, MS (m/z) 509 (M+H)⁺.

Tert-butyl(S)-(4-(3-(4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2,2-dimethylbut-3-yn-1-yl)carbamate(I-240)

¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=7.2 Hz, 1H), 7.86 (s, 1H),7.46 (s, 1H), 7.29-7.21 (m, 2H), 7.13-7.03 (m, 2H), 6.77 (t, J=8.5 Hz,2H), 4.92-4.79 (m, 1H), 4.65 (dd, J=9.8, 7.3 Hz, 1H), 4.28 (dd, J=11.3,9.8 Hz, 1H), 3.76 (s, 2H), 3.40 (s, 3H), 3.19 (d, J=6.5 Hz, 2H), 1.43(s, 9H), 1.27 (s, 6H). ¹³C NMR (101 MHz, Chloroform-d) δ 168.40, 162.41(dd, J=115.8, 11.9 Hz), 159.94 (dd, J=116.5, 11.9 Hz), 156.08, 149.56,148.97, 142.92, 135.94, 132.27-131.80 (m), 131.00, 130.98-130.79 (m),128.49 (d, J=12.1 Hz), 126.74, 126.51, 122.94, 122.86-122.58 (m),122.41, 121.12, 111.25 (dd, J=21.0, 3.7 Hz), 103.90 (t, J=25.6 Hz),95.80, 79.85, 79.37, 77.10, 50.84, 49.97, 35.49, 33.43, 28.34, 26.44,23.17. ¹⁹F NMR (376 MHz, Chloroform-d) δ−112.37 (p, J=7.5 Hz), −113.81(q, J=8.5 Hz). LCMS: Purity 98%, MS (m/z) 508 (M−Boc+H)⁺.

(S)—N-(7-(4-Amino-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(2,4-difluorobenzyl)-1H-pyrazole-1-carboxamidehydrochloride (I-241)

¹H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=6.6 Hz, 1H), 8.14 (s, 3H), 7.99(s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.38-7.27 (m, 2H), 7.24-7.11 (m,2H), 6.99 (t, J=8.6 Hz, 1H), 4.72-4.60 (m, 2H), 4.41 (d, J=5.4 Hz, 1H),3.78 (s, 2H), 3.27 (s, 3H), 2.91 (s, 2H), 1.32 (s, 6H). ¹⁹F NMR (376MHz, DMSO-d6) δ−112.67-112.85 (m), −114.02 (q, J=9.0 Hz). LCMS: Purity98%, MS (m/z) 508 (M−HCl+H)⁺.

(S)—N-(5-Methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(II-27)

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.74 (d, J=7.4 Hz, 1H), 8.48(d, J=5.6 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.34-7.25(m, 1H), 7.14-7.09 (m, 2H), 7.07 (d, J=8.8 Hz, 1H), 6.99 (dd, J=5.6, 2.6Hz, 1H), 6.80 (dd, J=8.8, 2.9 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.97 (dt,J=11.1, 7.4 Hz, 1H), 4.63 (dd, J=9.7, 7.5 Hz, 1H), 4.16 (dd, J=11.1, 9.7Hz, 1H), 3.40 (s, 3H), 3.18-3.10 (app m, 4H), 2.41-2.34 (app m, 4H),2.26 (s, 3H), 1.66-1.54 (m, 8H). LCMS: Purity 98%, MS (m/e) 556 (M+H)⁺.

tert-Butyl 4-benzyl-1H-pyrazole-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J=0.9 Hz, 1H), 7.55 (d, J=0.9Hz, 1H), 7.30 (dd, J=8.1, 6.6 Hz, 2H), 7.26-7.13 (m, 3H), 3.82 (s, 2H),1.63 (s, 9H).

LCMS: Purity 96%, MS (m/e) 282 (M+Na)⁺

4-Benzyl-1H-pyrazole hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (br s, 2H), 7.65 (s, 2H), 7.36-7.04(m, 5H), 3.79 (s, 2H).

LCMS: Purity 99%, MS (m/e) 159 (M−HCl+H)⁺

tert-Butyl 4-benzyl-3,5-dimethyl-1H-pyrazole-1-carboxylate

¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.31-7.23 (m, 2H), 7.22-7.14(m, 1H), 7.14-7.07 (m, 2H), 3.74 (s, 2H), 2.43 (s, 3H), 2.10 (s, 3H),1.62 (app s, 9H).

LCMS: Purity 97%, MS (m/e) 309 (M+Na)⁺

4-Benzyl-3,5-dimethyl-1H-pyrazole hydrochloride

¹H NMR (400 MHz, Chloroform-d) δ 7.33-7.24 (m, 2H), 7.27-7.18 (m, 1H),7.08-7.00 (m, 2H), 3.78 (s, 2H), 2.37 (s, 6H).

LCMS: Purity 99%, MS (m/e) 187 (M−HCl+H)⁺

tert-Butyl 4-(4-fluorobenzyl)-1H-pyrazole-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 7.81 (q, J=0.9 Hz, 1H), 7.53 (d, J=0.8Hz, 1H), 7.19-7.09 (m, 2H), 7.04-6.93 (m, 2H), 3.79 (s, 2H), 1.63 (s,9H).

LCMS: Purity 99%, MS (m/e) 177 (M−Boc+H)⁺

4-(4-Fluorobenzyl)-1H-pyrazole hydrochloride

1H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 2H), 7.64 (s, 2H), 7.29-7.14 (m,2H), 7.14-6.97 (m, 2H), 3.78 (s, 2H).

LCMS: Purity 99%, MS (m/e) 177 (M−HCl+H)⁺

tert-Butyl 4-benzyl-3-methyl-1H-pyrazole-1-carboxylate

1H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.32-7.26 (m, 2H),7.25-7.18 (m, 1H), 7.19-7.12 (m, 2H), 3.75 (s, 2H), 2.18 (s, 3H), 1.62(s, 9H).

LCMS: Purity 98%, MS (m/e) 295 (M+Na)⁺

4-Benzyl-5-methyl-1H-pyrazole

1H NMR (400 MHz, Chloroform-d) δ 7.53 (app s, 1H), 7.36-7.27 (m, 2H),7.29-7.21 (m, 1H), 7.15-7.08 (m, 2H), 3.81 (s, 2H), 2.42 (s, 3H).

LCMS: Purity 98%, MS (m/e) 173 (M−HCl+H)⁺.

tert-Butyl 3-(4-fluorobenzyl)-1H-pyrazole-1-carboxylate

1H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J=2.8, 0.7 Hz, 1H), 7.25-7.12(m, 2H), 7.06-6.84 (m, 2H), 6.06 (dd, J=2.8, 0.7 Hz, 1H), 4.00 (s, 2H),1.64 (d, J=1.1 Hz, 9H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−116.79 (ddd,J=14.2, 9.0, 5.3 Hz).

LCMS: Purity 95%, MS (m/e) 299 (M+Na)⁺

3-(4-Fluorobenzyl)-1H-pyrazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (br s, 2H), 7.77 (d, J=2.2 Hz, 1H),7.33-7.23 (m, 2H), 7.16-7.05 (m, 2H), 6.20 (d, J=2.2 Hz, 1H), 3.98 (s,2H).

LCMS: Purity 96%, MS (m/e) 177 (M−HCl+H)⁺

Example 31

In this example, compounds of the disclosure were evaluated using abiochemical assay using the ADP-Glo™ technology.

ADP-Glo™ (Promega, Madison, Wis., USA) reagents were thawed at ambienttemperature. Kinase Detection Reagent was prepared by mixing kinasedetection buffer with the lyophilized kinase detection substrate.

A 500 ml stock volume of 5× Reaction Kinase Buffer was made by mixing1000 μl of 1M MgCl₂, 500 μl of 1M Tris-HCL pH7.4, 0.5 mg/ml (25 mg) ofBSA, and 3475 μl of distilled H₂O. A 3 ml 2× working stock volume ofReaction Kinase Buffer was made containing a final concentration of 100μM DTT and 4 mM MnCl₂.

Components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco,Calif., USA) were thawed on ice. Diluted RIPK1 was prepared in 1× KinaseReaction Buffer (diluted from 2× buffer) to 31 ng/well. A 166 μM workingstock ATP assay solution was prepared in 1× Kinase Reaction Buffer(diluted from 2× buffer).

Compounds were serially diluted in DMSO from 250 uM in 4-fold dilutionsthen diluted 1:5 in 2× Reaction Buffer in a 96 well plate. 1.0 μl ofdiluted compound was added to a 384 well plate in duplicate. 2 μl ofdiluted Active RIPK1 was added to 384 well plate (do not add tocolumn 1) add 2× rxn buffer to column 1. AKT (Anaspec, Fremont, Calif.,USA) at 150 nM was combined with ATP working stock at equal volume and 2ul/well were added to the 384 well plate. The final reaction volume was5.0ul.

The plate was quickly centrifuged and the reaction was incubated at 30°C. for 30 minutes. Adding 5 μl of ADP-Glo™ terminated the reaction. Theplate was quickly centrifuged and the reaction was incubated at roomtemperature for 40 minutes. Kinase Detection Reagent was then added andincubated at room temperature for 30 minutes. The relative light unit(RLU) of kinase reaction was determined by luminescent (Luminescence 0.1s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, Mass.,USA).

IC₅₀ values obtained from this example are provided by Table 1.

TABLE 1 RIPK1 ADP-Glo Kinase Compound (IC₅₀) I-1 0.019 I-2 0.0157 I-30.0402 I-4 0.0568 I-5 0.0197 I-6 0.0724 I-7 0.021 I-8 0.0529 I-9 0.1892I-10 0.0429 I-11 0.0571 I-12 0.052 I-13 0.0539 I-14 0.073 I-15 0.1359I-16 1.633 I-17 0.4906 I-18 0.1645 I-19 0.1455 I-20 0.1528 I-21 0.077I-22 0.048 I-23 0.0352 I-24 0.0592 I-25 0.051 I-26 0.0656 I-27 0.1583I-28 0.0375 I-29 0.0124 I-30 0.0402 I-31 0.0334 I-32 0.0219 I-33 0.0145I-34 0.0492 I-35 0.0223 I-36 0.0338 I-37 0.0565 I-38 0.068 I-39 0.0364I-40 0.0887 I-41 0.08 I-42 0.0477 I-43 0.0854 I-44 0.034 I-45 0.0825I-46 0.0437 I-47 0.0683 I-48 0.0624 I-49 0.0604 I-50 0.0234 I-51 0.0317I-52 0.0249 I-53 0.034 I-54 0.0269 I-55 0.0337 I-57 0.0215 I-58 0.011I-59 0.0579 I-60 0.0644 I-61 0.0654 I-62 0.0355 I-63 0.0303 I-64 0.019I-65 0.0639 I-66 0.0794 I-67 0.0415 I-68 0.0222 I-69 0.0286 I-70 1.155I-71 0.0217 I-73 0.0429 I-74 0.0518 I-75 0.0546 I-76 0.0449 I-77 0.0327I-78 0.0334 I-79 0.0347 I-80 0.0206 I-81 0.019 I-82 0.0255 I-83 0.0664I-84 0.0441 I-85 0.0423 I-86 0.6161 I-87 0.0187 I-88 0.0738 I-89 0.0527I-90 0.3649 I-91 0.3879 I-92 0.9325 I-93 0.0641 I-94 0.0333 I-95 0.0271I-96 0.0317 I-97 0.0858 I-98 0.0296 I-99 0.1258 I-100 0.0392 I-1010.1332 I-102 0.3833 I-103 0.049 I-104 0.581 I-105 0.0312 I-106 0.5819I-107 0.0231 I-108 0.3137 I-109 0.0321 I-110 0.021 I-111 0.0218 I-1120.0151 I-113 1.002 I-114 0.0202 I-115 0.024 I-116 0.0234 I-117 0.0316I-118 0.0276 I-119 0.0598 I-120 0.0296 I-121 12.4 I-122 12.3 I-1230.0357 I-124 0.0935 I-125 0.0262 I-126 0.0246 I-127 0.0296 I-128 0.0197I-129 0.0352 I-130 0.0308 I-131 0.4455 I-132 0.0305 I-133 0.1727 I-1340.0528 I-135 0.1107 I-136 0.0267 I-137 0.0236 I-138 0.0769 I-139 0.0212I-140 0.1244 I-141 0.4141 I-142 0.0242 I-143 0.0279 I-144 0.022 I-1450.0275 I-146 0.0173 I-147 0.0173 I-148 0.0337 I-149 0.0396 I-150 0.0447I-151 0.0554 I-152 0.0103 I-153 0.0326 I-154 0.0267 I-155 0.0246 I-1560.0273 I-157 0.0316 I-158 0.0147 I-159 0.0175 I-160 0.0253 I-161 0.0362I-162 0.0544 I-163 0.5086 I-164 0.0717 I-165 0.0112 I-166 ND I-1670.0175 I-168 ND I-169 ND I-170 ND I-171 ND I-172 ND I-173 ND I-174 NDI-175 0.0278 I-190 0.0145 I-191 0.0197 I-206 0.0556 I-207 0.0279 I-2080.0172 I-209 0.1064 I-193 0.0553 I-194 0.0186 I-195 0.0153 I-210 0.0286I-196 ND I-197 ND I-203 0.0234 I-198 ND I-211 ND I-199 ND I-200 ND I-2120.1535 I-213 0.0352 I-214 0.0762 I-215 0.0321 I-216 0.0188 I-217 0.0239I-218 0.0245 I-219 0.0284 I-220 0.0355 I-221 0.0397 I-222 0.0166 I-2230.1411 I-224 0.3124 I-225 0.0227 I-226 0.033 I-235 0.0621 I-236 0.0559I-237 0.0431 I-240 0.2653 I-241 0.0501 II-16 0.0452 II-17 0.5184 II-180.0518 II-19 0.0349 II-20 0.0403 II-21 0.0409 II-22 0.3104 II-23 1.277II-24 0.0563 II-25 0.2258 II-26 0.193 II-27 0.0279 II-28 0.0161 II-310.0363 II-32 0.0505 II-33 0.1006 II-35 0.0275 II-36 0.0389 II-39 0.023

Example 32

In this example, U937 and L929 cells were exposed to compounds of thepresent disclosure and a cell necroptosis assay was conducted toevaluate the compounds' activity against human RIP1 and murine RIP1.

U937 and L929 cells were obtained from the American Type CultureCollection (Manassa, Va., USA). Both cells were maintained inlogarithmic growth phase in complete RPMI 1640 media (Sigma, ST Louis,Mo., USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis,Mo., USA) at 37° C. with 5% CO₂. For necroptosis assay, L929 cells wereplated for 18 h in 100 μL/well medium at 10K cells/well in Costar96-well black clear-bottom plates (Fisher Scientific, Hampton, N.H.,USA); U937 cells were plated on the day of the assay in 50 4/well mediumcontaining 60 uM zVAD-fink (Lonza, Basel, Switzerland) at 50Kcells/well. Medium from L929 cells were removed from the 96-well platesand replaced with 50 μL/well new medium containing 40 uM zVAD-fink. Eachcompound of the present disclosure evaluated in this example wasserially diluted in DMSO from 2.5 mM in 4-fold dilutions, and thendiluted 1:125 in complete medium. 50 μL/well 2× of the compound was thenadded to the cells in the plates. The cells were pre-incubated with thecompound for 1 hour at 37° C. with 5% CO₂ and before addition of 10μL/well 1 1×TNFa (Peprotech, Rocky Hill, N.J., USA) to give a finalconcentration of 2 ng/mL for TNFa. The relative amount of necroptosiscells was determined by luminescent using a Wallac Victor2 Luminometer(PerkinElmer, Waltham, Mass., USA) and a CellTiter-Glo® Luminescent CellViability Reagent Assay (Promega, Madison, Wis., USA) added permanufacturer instructions after 18 hours of TNFa stimulation at 37° C.with 5% CO₂. Results from this example are summarized in Table 2. Thisexample establishes that embodiments of the compounds described hereinhave unexpectedly potent activity against human RIP1 and murine RIP1,which allows their assessment in in vivo mouse models of disease. Theseresults are useful in determining safe and effective doses for humans.

TABLE 2 U937 Zvad L929-CTG- TNF CTG recovery, L929, Recovery, U937,TNFa + zVAD TNFa + zVAD Compound (IC₅₀) (IC₅₀) I-1 2.356 0.0027 I-2 ND0.0319 I-3 0.4278 0.0049 I-4 ND 0.0293 I-5 0.0188 0.0005 I-6 97.540.0438 I-7 1.959 0.0009 I-8 0.0092 0.0014 I-9 ND 0.3623 I-10 11.230.0079 I-11 14.1 0.0081 I-12 41.95 0.0053 I-13 ND 0.0138 I-14 5.8780.0114 I-15 2.2 0.0048 I-16 5.669 0.0517 I-17 0.3683 0.0024 I-18 0.27970.0013 I-19 1.302 0.0027 I-20 53.37 0.0136 I-21 1.306 0.0025 I-22 3.3830.0048 I-23 14.5 0.0067 I-24 4.608 0.0036 I-25 0.4895 0.0027 I-26 0.61310.0044 I-27 ND 0.0697 I-28 0.6735 0.0054 I-29 0.0088 0.0023 I-30 0.07230.0036 I-31 ND 0.0337 I-32 17.74 0.0027 I-33 1.227 0.0015 I-34 9.5920.0222 I-35 0.0178 0.0031 I-36 0.0014 0.0022 I-37 0.0002 0.001 I-380.0005 0.0036 I-39 0.0004 0.0027 I-40 0.0003 0.0023 I-41 0.0016 0.0052I-42 0.0012 0.0033 I-43 0.0009 0.0038 I-44 0.0002 0.0011 I-45 0.00030.0014 I-46 0.0004 0.0012 I-47 0.0015 0.0046 I-48 0.0005 0.0016 I-490.0012 0.005 I-50 0.0003 0.0011 I-51 0.0005 0.0017 I-52 0.0003 0.0009I-53 0.0005 0.0018 I-54 0.0003 0.0009 I-55 0.0006 0.002 I-57 0.00090.003 I-58 0.0002 0.0008 I-59 0.0007 0.0019 I-60 0.0024 0.0048 I-610.0013 0.0034 I-62 0.0007 0.002 I-63 0.0003 0.001 I-64 0.0001 0.0005I-65 0.0415 0.042 I-66 0.0949 0.1886 I-67 0.0085 0.0152 I-68 0.00030.0007 I-69 0.0009 0.0022 I-70 0.0195 0.1876 I-71 0.0002 0.0009 I-730.0027 0.0117 I-74 0.0002 0.0014 I-75 0.0014 0.0083 I-76 0.0024 0.0181I-77 0.0003 0.0028 I-78 0.0009 0.0025 I-79 0.0008 0.0051 I-80 0.00070.0027 I-81 0.0012 0.0042 I-82 0.0003 0.0019 I-83 0.0001 0.001 I-840.0122 0.0563 I-85 0.0006 0.0033 I-86 0.0006 0.0041 I-87 0.0292 0.1385I-88 0.00009757 0.0007 I-89 0.0007 0.0045 I-90 0.0046 0.0091 I-91 0.00370.0198 I-92 0.4305 4.835 I-93 0.9207 3.238 I-94 0.0046 0.022 I-95 0.00050.0014 I-96 0.0008 0.0031 I-97 0.0009 0.0017 I-98 0.0368 0.0016 I-990.116 0.0013 I-100 0.2634 0.0083 I-101 0.6682 0.0363 I-102 0.3972 0.0273I-103 0.0674 0.0015 I-104 1.818 0.2236 I-105 0.2537 0.0093 I-106 0.48060.0055 I-107 0.1614 0.0013 I-108 2.309 0.0088 I-109 0.0243 0.0004 I-1100.0188 0.0004 I-111 0.0999 0.0031 I-112 0.0142 0.0011 I-113 2.34 0.0315I-114 0.0904 0.0047 I-115 0.0491 0.0008 I-116 0.1356 0.0007 I-117 0.01120.0002 I-118 0.083 0.001 I-119 4.054 0.0146 I-120 0.0615 0.0005 I-121ND* 30.31 I-122 ND* 40.39 I-123 0.0535 0.0006 I-124 2.117 0.0887 I-1250.1157 0.0098 I-126 0.0553 0.0035 I-127 0.0406 0.0003 I-128 0.04220.0006 I-129 0.0241 0.0007 I-130 0.0895 0.0015 I-131 0.0658 0.0037 I-1324.603 0.0359 I-133 ND* 0.4924 I-134 0.6079 0.0274 I-135 2.63 0.2241I-136 4.969 0.0152 I-137 0.3329 0.005 I-138 3.146 0.1223 I-139 0.53840.0077 I-140 0.1086 0.0046 I-141 0.1203 0.0022 I-142 0.0773 0.0014 I-1430.1973 0.0035 I-144 0.1565 0.0012 I-145 3.049 0.0086 I-146 0.0183 0.0004I-147 0.1537 0.0012 I-148 0.3591 0.0052 I-149 11.57 0.03 I-150 ND*0.0831 I-151 1.081 0.017 I-152 2.509 0.0391 I-153 1.238 0.0161 I-1540.6564 0.0035 I-155 0.3127 0.0013 I-156 10.26 0.0554 I-157 5.161 0.0255I-158 1.645 0.0095 I-159 16.07 0.021 I-160 0.0442 0.0009 I-161 50610.0455 I-162 ND* 1.656 I-163 ND* 3.317 I-164 0.0319 0.0007 I-165 0.04710.0009 I-166 0.0277 0.001 I-167 1.211 0.0053 I-168 0.103 0.0009 I-1690.148 0.0022 I-170 1.835 0.0148 I-171 0.3943 0.0064 I-172 0.8495 0.0221I-173 2.863 0.0485 I-174 16.52 0.4379 I-175 0.1072 0.009 I-190 0.02050.0006 I-191 0.0215 0.0003 I-206 0.0415 0.0006 I-207 0.1158 0.0005 I-2080.0975 0.0006 I-209 5001 0.0595 I-193 7.062 0.3612 I-194 0.0325 0.0006I-195 0.2683 0.0011 I-210 0.4701 0.0042 I-196 0.201 0.0033 I-197 0.07060.0007 I-203 0.004 0.0004 I-198 0.0391 0.0009 I-211 0.0448 0.0011 I-2120.2674 0.0043 I-213 0.0455 0.001 I-214 0.3515 0.004 I-215 0.0209 0.0003I-216 0.0285 0.0005 I-217 0.5968 0.0005 I-218 0.0758 0.0026 I-219 0.02360.0006 I-220 1.921 0.0089 I-221 0.0722 0.0025 I-222 0.0625 0.0014 I-22310.34 0.6274 I-224 0.2203 0.0015 I-225 0.0325 0.0005 I-226 1.773 0.017I-235 1.071 0.0132 I-236 0.2583 0.0066 I-237 15.53 0.135 I-239 0.21780.0088 I-240 0.9435 0.0151 I-241 2.095 0.0626 II-16 2.122 0.0034 II-17ND 1.492 II-18 6.638 0.2864 II-19 2.894 0.0555 II-20 14.62 0.0316 II-213.442 0.0143 II-22 55.98 0.5803 II-23 ND 0.5449 II-24 7.912 0.0166 II-250.2023 0.0024 II-26 ND 0.5101 II-27 10.45 0.0633 II-28 2.22 0.0083 II-310.6543 0.008 II-32 0.0574 0.0021 II-33 0.0331 0.0018 II-35 0.1643 0.0007II-36 0.1316 0.0016 II-39 1.348 0.0018 *ND indicates that no activitywas detected or that the inhibition curve showed artifacts. This valuedoes not necessarily indicate an inactive compound, but indicates thatthe experiment failed to yield data for some reason. By way of example,an insoluble compound or other experimental artifact can result in a“ND” value.

Example 33

In this example, an acute hypothermia mouse model assay was used toevaluate the ability of compounds disclosed herein to inhibit TNF-alphainduced hypothermia.

Female C57BL/6 mice are randomly grouped and weighed on Day −1. On theday of the study (Day 0), mice are administered vehicle or test articleby oral gavage. Fifteen minutes after oral administration of testagents, each mouse is administered an intraperitoneal (IP) injection ofsolution containing recombinant human tumor necrosis factor alpha(TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature is measured at0 hours (before IP injections) and every hour via rectal probetemperature measuring device. Three (3) hours after IP injections ofTNF-α and zVAD/FMK, mice are euthanized by CO₂ asphyxiation and blood iscollected via cardiac puncture. Serum and plasma are harvested fordetermination of cytokine and compound levels, respectively. Separategroups of mice (satellite mice) are included for the determination ofcompound levels in plasma at the time of administration ofTNFa/zVAD-FMK.

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(WO 2014/125444), having a structure as illustrated below, was used as acomparative compound and was examined using a similar protocol asdescribed by WO 2014/125444. This comparative compound exhibited 93%inhibition at a dose of 30 mg/kg according to WO 2014/125444; however,in the inventors hands, the compound inhibited only 70% at 30 mg/kg. Incomparison, compound I-30 of the present disclosure achieved greaterthan 85% inhibition at a dose of just 5 mg/kg using the similar assayprotocol described above.

Certain embodiments of the disclosure provide for compound, compounds orcompositions thereof to traverse the blood-brain barrier. Disclosedcompound and composition embodiments exhibit sufficient brainpenetration as potential therapeutics in neurological diseases. Brainpenetration may be assessed by evaluating free brain/plasma ratio(Bu/Pu) as measured in vivo pharmacokinetic studies in rodents. Othermethods for assessing brain penetration are known to persons of ordinaryskill in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp.Therap., 325:349-56, 2008.

Table 3 below provides additional biological data for representativecompounds according to the present disclosure.

TABLE 3 BRAIN PLASMA Ratio COMPOUND Cl T1/2 Vss AUC₀₋₆ AUC₀₋₆(Brain/Plasma) I-180 151.0 2.3 16.4 103 251 2.44 I-127 94.8 2.1 9.2 164160 0.98 I-181 16.4 1.1 1.0 1000 456 0.46 I-182 57.7 1.4 5.2 280 1570.56 I-183 40.7 3.0 5.5 361 326 0.90 I-184 19.0 2.4 2.6 783 731 0.93I-137 40.6 1.3 4.0 396 — — I-139 16.9 2.6 2.7 856 1100 1.29 I-185 11.72.7 2.6 1140 418 0.37 I-155 64.4 2.3 11.9 220 373 1.70

In view of the many possible embodiments to which the principles of thepresent disclosure may be applied, it should be recognized that theillustrated embodiments are only preferred examples and should not betaken as limiting. Rather, the scope of the present disclosure isdefined by the following claims. We therefore claim as our invention allthat comes within the scope and spirit of these claims.

We claim:
 1. A compound, having a formula

or a pharmaceutically acceptable salt thereof.
 2. A compound, having aformula

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1 which is:


4. The compound according to claim 2 which is:


5. A pharmaceutical composition, comprising a compound having theformula:

or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 6. The pharmaceutical compositionaccording to claim 5 wherein the compound is:


7. A pharmaceutical composition, comprising a compound having theformula:

or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 8. The pharmaceutical compositionaccording to claim 7 wherein the compound is: